Articles

Article

Review Article

Exp Neurobiol 2014; 23(4): 277-291

Published online December 31, 2014

https://doi.org/10.5607/en.2014.23.4.277

© The Korean Society for Brain and Neural Sciences

Multiple System Atrophy: Genetic or Epigenetic?

Edith Sturm and Nadia Stefanova*

Division of Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck A-6020, Austria

Correspondence to: *To whom correspondence should be addressed.
TEL: 43-512-50424363, FAX: 43-512-50424230
e-mail: nadia.stefanova@i-med.ac.at

Received: September 5, 2014; Revised: September 29, 2014; Accepted: September 29, 2014

Multiple system atrophy (MSA) is a rare, late-onset and fatal neurodegenerative disease including multisystem neurodegeneration and the formation of α-synuclein containing oligodendroglial cytoplasmic inclusions (GCIs), which present the hallmark of the disease. MSA is considered to be a sporadic disease; however certain genetic aspects have been studied during the last years in order to shed light on the largely unknown etiology and pathogenesis of the disease. Epidemiological studies focused on the possible impact of environmental factors on MSA disease development. This article gives an overview on the findings from genetic and epigenetic studies on MSA and discusses the role of genetic or epigenetic factors in disease pathogenesis.

Keywords: Multiple system atrophy, α-synuclein, neurodegeneration, genetics, epigenetics

In 1969 Graham and Oppenheimer suggested the term "multiple system atrophy" (MSA) to describe and combine a set of different disorders, including olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome [1]. MSA is nowadays considered to be a rare, late-onset and fatal neurodegenerative disease with a largely unknown etiopathogenesis. Prevalence ranges from 1.9 to 4.9 per 100,000 inhabitants, incidence is about 0.6 per 100,000 per year or rather 3 per 100,000 per year in the population over 50 years [2, 3]. Patients show an average disease onset of 60 years (SD=9; range: 34 to 83 years), affecting males and females equally [4]; mean disease duration is between 7 to 9 years after clinical presentation [5]. This movement disorder is clinically represented by atypical parkinsonism, cerebellar ataxia, pyramidal signs, and always accompanied by autonomic failure; pathologically MSA is characterized by selective wide spread neuronal cell loss, gliosis and oligodendroglial cytoplasmic inclusions (GCIs) affecting several structures of the central nervous system [3, 6, 7].

Neuronal loss in MSA affects the striatum, substantia nigra pars compacta (SNpc), cerebellum, pons, inferior olives, central autonomic nuclei and the intermediolateral column of the spinal cord [8]. Microglial and astroglial activation (gliosis) affecting several regions of the MSA brain could partly be triggered by oligodendroglial α-synuclein pathology, but the exact pathogenic mechanisms need to be further clarified [9, 10, 11, 12]. GCIs represent the major pathological hallmark of the disease [7] and are mostly containing misfolded, hyperphosphorylated (affecting residue Ser129) and fibrillar α-synuclein [13, 14, 15]. GCIs also contain tau, 14-3-3 protein, LRRK2, parkin, heat shock protein family members Hsp70 and Hsc70, p25α, α-tubulin, β-tubulin, microtubule associated proteins and cycline dependent kinase 5 (cdk5) among others [16, 17, 18, 19, 20 ,21, 22, 23]. The mechanisms of GCI formation in MSA remain unclear; two hypotheses try to explain. The first suggests that active uptake of α-synuclein from neighboring neurons by oligodendroglia could take place. Whereas the second hypothesis states that there could be a selective increase of α-synuclein expression in oligodendroglial cells in MSA [24]. Disturbed protein degradation may further contribute to the accumulation of α-synuclein in MSA oligodendrocytes [25]. Since the etiology and pathogenesis of MSA are not completely understood, no effective therapies have been established up to date to cure MSA. In 2009, the discovery of α-synuclein gene (SNCA) variants association with an increased risk for MSA especially in Caucasians suggested an important lead in the role of genetic predisposition in MSA [26]. Along with the fact that MSA has always been considered to be a sporadic disease [27], this was thought to be a great breakthrough. Since then, many studies have been performed with the aim to detect disease-causing or disease-linked genes and gene variants. Other studies focused on environmental risk factors and epigenetic mechanisms, since MSA shares common features with other neurodegenerative disorders that have proven role of epigenetic modifications in their pathogenesis [28]. Within this article, we provide an update on recent studies concerning genetic and epigenetic factors that might be involved in MSA etiology and pathogenesis.

Familial MSA

MSA is a typically sporadic neurodegenerative disease [27], but rare cases exist presenting a family history of MSA [29, 30, 31, 32, 33]. The ancestry arrangement in two of those family cases - probable MSA in one German and one Japanese family - [30, 32, 33] is consistent with typical autosomal dominant inheritance. Four different Japanese families with multiple affected siblings show probable autosomal recessive inheritance [29]. In 2012, a case of two sisters from the US was reported, presenting similar syndromes of MSA and thereby suggesting autosomal dominant inheritance [31]. Recently, two Japanese siblings (affected with either probable MSA-C and definite MSA-P) were described. Inheritance was found to be autosomal recessive, even though no consanguineous marriage took place and no genetic mutations were identified [34]. So far, no disease-causing and hereditable mutations have been definitely identified in MSA.

Potential genetic "hotspots"

SNCA - mutations, multiplications, SNP variants and the possible risk to develop MSA

Since the pathological hallmark of MSA is represented by GCIs [7] containing mostly α-synuclein among other components, MSA together with Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) is considered to be an α-synucleinopathy [13]. The fundamental role of α-synuclein in MSA pathogenesis leads to the suggestion that there might be a connection between possible SNCA variants and a risk for developing MSA. Several genetic approaches have been undertaken addressing this particular question.

Discovered in 1997, A53T has been the first SNCA point mutation identified in families with autosomal dominant PD [35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49]. This was followed by the identification of A30P [35, 44, 50, 51] and E46K point mutations of the SNCA gene in familial PD cases [52]. In vitro as well as in vivo experiments in PD models showed that those mutations promote the aggregation of α-synuclein [53, 54, 55]. In silico experiments demonstrated that A18T and A29S were associated with sporadic forms of PD and similarly accelerate α-synuclein aggregation [56]. Recently two novel substitutions in SNCA, H50Q [57, 58, 59, 60, 61] and G51D [59, 60, 62, 63], have been described. H50Q was associated with increased α-synuclein aggregation, secretion and extracellular toxicity [59, 60, 61]. Interestingly, G51D has an opposite effect on the aggregation behavior of α-synuclein, thereby reducing aggregation effects, accompanied with impaired membrane binding and enrichment of the mutant in the nuclear compartment [59, 63]. Consequently, different groups attempted to detect an association between SNCA gene mutations and MSA, but these efforts remained futile. It was suggested that transcriptional alterations of SNCA using bigger sample sizes with higher statistical power should be investigated [64, 65, 66, 67]. Yet, no mutations in the coding region of SNCA have been identified in pathologically proven MSA cases [64]. A patient with the G51D substitution showed clinical, genetic and neuropathological characteristics of an α-synucleinopathy including PD and MSA-like features including widespread neuronal and GCI-like oligodendroglial inclusions, neuronal loss in substantia nigra, locus coeruleus, hippocampal CA2/3 subregions, frontal and temporal cortices, dorsal motor nucleus of the vagus and striatum [62]. The observed features were found to be similar to those in cases with A53T mutations and SNCA polymorphism cases [68, 69]. It was therefore suggested that the G51D substitution of the SNCA gene could be a possible link between PD and MSA. This idea was further supported by the detection of the novel A53E SNCA substitution in a Finnish patient presenting both atypical PD as well as MSA features [70]. In relation to the findings of SNCA multiplications in PD, Fuchs and colleagues found that duplications and triplications of SNCA are leading to MSA-like features in autosomal dominant PD [71]. However, a targeted search of SNCA multiplications in 58 pathologically confirmed MSA cases failed to confirm the role in MSA [66].

In 2009, the single nucleotide polymorphism (SNP) study in SNCA by Scholz and colleagues suggested the first genetic SNCA variants that were associated with increased MSA risk in Caucasian patients. Two SNPs at the SNCA locus were found: rs11931074 (p-value in recessive model = 1.4 × 10-11) and rs3857059 (p-value in recessive model = 4.9 × 10-6) with increased frequency in MSA. The authors stated that those variants might lead to pathogenic α-synuclein accumulation by alteration of the SNCA splicing pattern and/or SNCA messenger RNA processing and/or by other genetic factors [26]. Interestingly, both SNCA variants are considered to be PD risk factors [72, 73]. Two further studies subsequently replicated the results from Scholz and colleagues [74, 75]. Another study focusing on Korean MSA patients failed to replicate the findings by Scholz and colleagues (p-value of rs11931074 in recessive model = 0.77) [76], suggesting a certain degree of heterogeneity within different ethnicities.

SNCA-linked genetic predisposition seems to play an important role in MSA but further studies are needed to identify the possible mechanisms underlying these interactions.

COQ2 mutations and MSA

COQ2 gene encodes the enzyme parahydroxybenzoatepolyprenyl transferase, which is important for the biosynthesis of coenzyme Q10 (CoQ10 or ubiquinone) [77]. Recently, the Multiple-System Atrophy Research Collaboration published an association between COQ2 mutations and an increased risk for developing MSA. By whole genome sequencing two mutations, M128V-V393A/M128V-V393A (homozygous) and R337X/V393A (heterozygous variant), were identified in two multiplex families with MSA. The V393A variant was shown to be common in sporadic MSA cases, Japanese patients only (allele frequency = 1.6 to 2.2%), thereby suggesting that it could serve as a potential risk factor for MSA-C. Finally it was concluded that mutations in the COQ2 gene would theoretically impair the mitochondrial respiratory chain and lead to less tolerance to oxidative stress, further resulting in a predisposition to MSA. The authors suggest possible efficacy of oral treatment with coenzyme Q10 in MSA [78, 79], since COQ2 mutations cause a lack of coenzyme Q10 [80]. Several studies in European and Korean MSA patients failed to detect COQ2 mutations [79, 81, 82, 83], thereby contradicting the findings of the MSA Research Collaboration with a Japanese lead. Additionally, a very recent case report on two MSA affected Japanese siblings also failed to identify any COQ2 mutations, neither the homozygous (M128V-V393A/M128V-V393A) nor the heterozygous (R337X/V393A) variant [34, 79]. It is assumed that COQ2 mutations may cause a higher vulnerability of the cerebellum to damages, including dysfunction and loss of oligodendrocytes in MSA [84], but the exact role on MSA etiology remains unclear and requires further investigation. In summary, it seems that the evidence of a direct association between COQ2 mutations and MSA is currently weak.

Genes related to spinocerebellar ataxias and MSA

MSA patients show overlapping features with autosomal dominant spinocerebellar ataxias (SCAs), including prominent ataxia, dysmetria and abnormal eye movement [85]. For this reason the investigation of possible SCA genocopies in MSA patients has been of great interest. Since 1996, many studies focused on the possible clinical overlap of SCAs and MSA [86, 87, 88, 89, 90]. Gilman et al. investigated four members of a family with SCA1 mutations presenting dominantly inheritated progressive ataxia, dystonia, autonomic dysfunction and peripheral neuropathy. Several unusual SCA1 but MSA-like symptoms were found including neurodegeneration of the basal ganglia, cerebellum, brainstem and the intermediolateral columns of the spinal cord as well as tau- and ubiquitin-positive GCIs. Yet, unusual MSA features like early disease onset, cerebellar and autonomic features in the absence of pyramidal or extrapyramidal signs were also detected. It was concluded that SCA1 gene mutations might only lead to a disorder mimicking MSA [86]. Although cases of SCA2 were identified to present with glial cytoplasmic inclusions these were α-synuclein-negative [91, 92]. A SCA3 patient showed additional neurodegenerative disorders resembling the pathological features of cerebellar MSA (MSA-C). The patient presented α-synuclein positive GCIs and neurodegeneration in the olivopontocerebellar, striatal and pyramidal motor regions [87], thereby meeting the criteria for definite MSA-C diagnosis [93]. A case-control study on Caucasian MSA patients (n=80) failed to confirm the presence of SCA3 expansions, highlighting that MSA is an autonomous disease, not related to SCA-gene mutations [94]. Furthers studies found SCA6, SCA8 and SCA17 genes to be related to MSA [88, 95, 96, 97], but others state that those as well as the SCA 1, 2, 3, 7 and 12 genes do not contribute to MSA etiology [97, 98]. Patients with FXTAS, which is caused by a CGG expansion in the X mental retardation 1 gene (FMR1) [99], often show clinical features that look like those of MSA-C [100, 101]. A possible connection between MSA and premutations (55-200 repeats) in the FMR1 gene was investigated in a study on Japanese MSA patients, but failed to support the initial assumption [102]. Additionally, the European MSA study group is not recommending FMR1 genotyping to diagnose MSA [90].

Other genetic risk loci and MSA

Several studies on mutated genes associated with MSA-related neurodegenerative disorders failed to identify a direct genetic link to MSA. Negative findings included: Parkin and PTEN-induced putative kinase 1 (PINK1) mutations causing autosomal recessive early-onset PD [103, 104, 105], genetic variants of MAPT encoding for the microtubule-associated protein tau [106, 107, 108], PD risk factors LRRK2 and GBA genes [26, 65, 109, 110, 111, 112, 113, 114] and other mutations in genes coding for apolipoprotein E, dopamine β-hydroxylase, ubiquitin C-terminal hydrolase-1 (UCH-1), fragile x mental retardation 1, leucine-rich kinase 2 (LRRK2), progranulin (PRGN) [115, 116, 117, 118], dopamine-β-hydroxylase (DBH) [119], CYP2D6 [120, 121, 122], BDNF, CNTF, IGF1, HLA and hiGIRK [94], PITX3 [123] and rs1572931 polymorphisms in the RAB7L1 gene [124].

Since gliosis accounts to MSA pathogenesis [6], several genes involved in inflammatory processes have been investigated. Microglia activation leads to the production of cytokines, including interleukin-1-α (IL-1-α), IL-1-β, IL-6 and tumor necrosis factor-α (TNF-α), as well as chemokines such as IL-8 and the inflammatory intercellular-adhesion molecule-1 (ICAM-1) [125]. Association with an increased risk to develop MSA was found in relation to gene polymorphisms in IL-1-α [126], IL-1-β [127], IL-8 and ICAM-1 [128], α-1-antichymotrypsin [98] and tumor necrosis factor genes [129]. Unfortunately, those studies include small patient numbers but they point out the possible pathogenic role of inflammation in MSA pathogenesis.

Since oxidative as well as nitrative stress are implicated in the progression of α-synucleinopathies, related factors have been tested and a link to MSA was found for SLC1A4, SQSTM1 and EIF4EBPI [130].

Genetic variability in alcohol dehydrogenase (ADH) gene risk factors was investigated in MSA. ADH1C G78X mutation was associated with MSA in British but not in German cohorts [131], whereas no connection of ADH7 variants has been found [132]. In 2009, a MSA patient was reported to have "muscular" pain, similar to myotonic dystrophy type 2 (DM2). Since this disease is associated with parkinsonism, DNA analyses were performed revealing mutations in the ZNF9 gene. However, no other MSA patients carrying this mutation have been reported so far [133, 134], thereby further studies are needed. For several years, there has been an ongoing discussion whether neurodegenerative diseases are prion-like diseases [135], supported by the finding of an intriguing MSA case with sporadic prion-like features. Genetic screening did not detect mutations in the prion protein gene (PRNP), but carried a well-established risk factor for Creutzfeldt-Jakob disease (M129V polymorphism in PRNP). A case control study investigated this risk factor and revealed an association with increased risk for MSA, when compared to PD, but not to the control group [136]. Very recently, hexanucelotide repeat expansions in C9orf72 were reported in a family presenting both MSA and amyotrophic lateral sclerosis (ALS), thereby highlighting a phenotypic variability of those expansions [137]. Sasaki and colleagues suggested a causal link between a copy number loss of (Src homology 2 domain containing)-transforming protein 2 (SHC2) and MSA [138, 139, 140]. However, Ferguson and colleagues contradicted these finding when examining MSA patients form the US [141].

In conclusions, the genetic studies in MSA to date do not support the use of genetic factors like SNCA, COQ2, SCAs expansions etc. to reliably diagnose MSA. Several gene polymorphisms have been linked to an increased risk for developing MSA, but many of the findings have been contradictory dependent on the high heterogeneity of the MSA patients. Further genetic analysis involving larger patients cohorts are warranted to provide reliable information on the role of selected genes in the etiopathogenesis of MSA.

Epigenetics and disease

Given the fact that it is still unclear whether genetics have a predisposing role in the etiology of MSA, several studies focused on the investigation of risk factors that could lead, together with genetic predisposition to disease development. Epigenetics includes transcriptional as well as post-transcriptional, reversible and hereditable changes to DNA that do not alter DNA sequence itself and regulate gene expression. The epigenetic machinery acts via different mechanisms. DNA-methylation includes the addition of a methyl group to the 5' carbon of cytosines, which are located to CpG islands in promoter regions (regions with high content of the bases cytosine and guanine) and associated with gene silencing. Histone modifications (acetylation, phosphorylation, methylation, ubiquitination or sumoylation) are carried out at the N-termini of the core histones that protrude from the nucleosome modulating gene expression and chromatin structure. RNA-mediated silencing pathways include non-coding RNAs as well as non-coding antisense RNAs, RNA interference and microRNAs (miRNAs). Together these epigenetic mechanisms form the "epigenetic landscape" being very dynamic, in contrast to irreversible genetic mutations, and can be influenced during life through environmental stimuli. Destruction of the epigenetic balance leads to several distinct diseases [142, 143]. Many disorders have already been connected to epigenetic alterations including cancer [144], cardiovascular diseases [145, 146], autoimmune disorders [147], metabolic diseases [148, 149], myopathies [150], learning and memory deficits [151, 152] and some neurodegenerative diseases [153].

There has been emerging evidence that neurodegenerative diseases are linked to exposure to chronic neurotoxic substances and other risk environmental factors resulting in a higher risk of disease development [154]. For example the risk to develop multiple sclerosis is increased when being infected with Epstein-Barr virus and smoking cigarettes, whereas vitamin D is protective [155]; Alzheimer's disease is associated with lead (Pb) exposure resulting in higher amounts of β-amyloid, stress and traumatic brain injuries [156, 157, 158, 159, 160]; higher risk to develop PD was linked among others to exposure to metals (Pb and others), certain chemicals and magnetic fields [161].

Given that MSA is a neurodegenerative disease as well as α-synucleinopathy with unclear genetic background, MSA patients have been investigated with regard to identify the role of environmental and epigenetic factors including stress, occupational and daily habits and exposure to toxins, metals, solvents, plastic monomers or additives, as well as history of farming.

Putative environmental risk factors in MSA

Exposures to metal dusts and fumes, plastic monomers and additives, organic solvents and pesticides have been linked significantly to a higher vulnerability of the nervous system supporting disease onset of MSA [162]. Recently, one case report supported the role of intensive and extended contact with organic solvents as a risk factor in MSA, as reported when examining a long-term professional painter [163]. A putative association to environmental toxins with MSA-like disorders has been shown, including inorganic mercury, methanol, carbon tetrachloride, carbon disulfide, cyanide, and manganese after heavy occupational exposure [164, 165]. Control studies confirmed the findings by detecting increased total iron levels in MSA and PD brains, but failed to detect alterations in manganese levels [166, 167, 168].

Epidemiological studies investigated the influence of farming on MSA, involving exposure to different chemicals and factors (pesticides, solvents, mycotoxins, dust, fuels, oils, fertilizers, animals) and a certain lifestyle (consummation of well water, rural living, diet and physical activity) [169]. Especially pesticides have been continuously associated with an increased risk of developing MSA, supported by independent studies [162, 170, 171]. So far, there is only one study contradicting these findings and stating that only plant and machine operators and assemblers develop an increased risk for MSA that is increasing with time of exposure [172].

The influence of smoking on MSA has been investigated already in 1986 and studies showed an inverse association with MSA [170, 173, 174]. Vanacore and colleagues also investigated effects of smoking together with farming on MSA concluding that those two risk factors are not interacting with the disease development (ever-smokers compared with never-smokers) [171]. In contrast to those findings, one MSA patient was reported recently having severe nicotine sensitivity. Interestingly, Graham and Oppenheimer described a similar case in 1969, but further studies are needed in order to investigate the prevalence of those cases in MSA [1, 175]. Regarding education, MSA patients seemed to have a lower educational level when compared to healthy controls [170, 172]. Concerning food habits, the consumption of meat has been associated with a higher risk of developing MSA. Other habits including drinking alcohol, aspirin use and fish or seafood consumption were found to be more common in healthy controls and are considered being protective factors. The same study was not able to confirm an effect of herbal tea or tropical fruits consumption, as it was suggested previously [172].

Until now, several risk factors have been associated with MSA. However, epidemiological studies display some limitations. Those studies are often affected by a certain recall bias (over-reporting of exposures) and selection bias (patients with severe disease are less able to participate) that influences the outcomes [176]. Therefore, further epidemiological studies of expanded cohorts are needed to get more data on potential MSA risk factors.

What is the evidence that epigenetics may play a role in MSA: recent findings

It has been shown that nutrients and environmental toxins, especially metals, are able to cause DNA methylation changes, histone modifications and RNA interference [177]. Together with findings on maternal nutrition that modulates gene expression already in the embryo supporting the possible development of later life diseases [178], this is pointing out the powerful influence of environmental factors on the epigenetic landscape and supporting the idea of a certain gene-environment interaction. Unfortunately not much is known about epigenetic modulations in MSA that could be provoked by environmental risk factors.

As mentioned, the epigenetic landscape is shaped by several mechanisms. DNA methylation changes have not been reported in MSA yet. Histone modifications can include acetylation, phosphorylation, methylation, ubiquitination or sumoylation of the four core histone proteins (H2A, H2B, H3, and H4) of the nucleosome. None of these has been studied in MSA patients to our knowledge. Specifically histone acetylation is controlled by a pair of antagonistic enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) that carry out acetylation and deacetylation at the N-termini of the nucleosomes, thereby modifying the histones. Histone deacetylation by HDACs influences gene expression, cell cycle regulation, chromatin structure and developmental events [179, 180, 181]. 18 different HDAC families are known in mammalians. The representative family members can be subdivided into zinc-dependent (HDAC1-11) and nicotinamide adenine dinucleotide (NAD+)-dependent (sirtuin 1-7) enzymes [182]. Miki and colleagues showed that patients with PD and dementia with Lewy bodies (DLB) show a co-localization of HDAC6 with Lewy bodies and also HDAC6 co-localized with GCIs in MSA brains [183], indicating a putative role of HDAC6 in MSA. Despite its name, the role of HDAC6 in histone deacetylation directly is unclear. HDAC6 is unique to a certain extent, since it possesses two functional catalytic sites at the N-terminus in combination with an ubiquitin-binding domain at the C-terminus. Although shuttling between the cytoplasm and the nucleus has been proposed, HDAC6 is found mainly in the cytoplasm, which is suggesting a histone-independent function [184].

The very first indications of a changed epigenetic landscape in MSA were provided just recently, by studies describing an altered expression of microRNAs in MSA. MicroRNAs (miRNAs) are small non-coding RNAs that are able to regulate gene expression post-transcriptionally [185] and important for the survival of mature neurons and their functions [186]. Ubhi and colleagues found an upregulation of the microRNA miR-96 in MSA patients, which is connected to a down-regulation of miR-96 target genes, including family members of the solute carrier protein family SLC1A1 and SLC6A6 [187]. A previous genetic association of SLC1A4 with MSA is supporting this finding [130]. Expression of miR-202 is upregulated in the cerebellum of MSA patients, consistent with reduced Oct1 protein expression. By that, miR-202 and the Oct1 pathway are thought to participate in sporadic cerebellar neurodegeneration representing a novel putative therapeutic target in MSA. The authors suggest that decreased Oct1 levels lead to higher vulnerability of neurons to oxidative stress [188], since this mechanism is involved in cerebellar neurodegeneration [189]. Next to miR-202, other microRNAs show downregulation (miR-129-3p, miR-129-5p, miR-337-3p, miR-380, miR-433, miR-132, miR-410, miR-206 and miR-409-5p) or upregulation (miR-199a-5p) in the cerebellum, but those findings need to be re-evaluated and confirmed in future studies [188]. A further study was able to identify circulating microRNAs (cimRNAs) to be differentially expressed in MSA and PD patients. MSA patients are distinguished from PD patients and healthy controls by an up-regulation of miR-24, miR-34b and miR-148b, whereas miR-339-5p is downregulated. [190]. The role of these changes is still unclear, however similar they show definite link to neurodegeneration. Previous studies showed that miR-339-5p is expressed at low levels in mature neurons and connected to axon guiding [191]; miR-24 is upregulated in multiple sclerosis and myocardial ischemia [192, 193]; miR-34b is connected to Huntington's disease, PD and Dementia with Lewy Bodies [194, 195]; miR-148b is downregulated in the parietal lobe cortex and hippocampal as well as medial frontal gyrus of Alzheimer's patients [196, 197].

So far, the underlying mechanisms of MSA etiopathogenesis are still elusive. Several familial MSA cases exist, but no hereditable mutations have been found supporting hereditary disease. COQ2 mutations have been proposed to associate with familial and sporadic MSA, however this observation could not be replicated in different patient cohorts. Investigations of other genetic "hotspots" linked SNCA polymorphisms with an increased risk of developing MSA in Caucasians. Further studies associated gene polymorphisms in IL-1-α, IL-1-β, IL-8, ICAM-1, α-1-antichymotrypsin, tumor necrosis factor genes, SLC1A4, SQSTM1 and EIF4EBPI with MSA predisposition, but failed to detect other disease-causing mutations. The genetic background of MSA thereby remains unclear, very much population-specific, and needs to be investigated further. Epidemiological studies investigated the potential influence of environmental factors on MSA pathogenesis. Exposures to metal dusts and fumes, plastic monomers and additives, organic solvents, pesticides and other environmental toxins have already been linked to a higher risk of MSA by changing the epigenetic landscape. However, the mechanisms of environmental epigenetics are not studied in depth in MSA and need further investigation as supported by the emerging evidence [198]. Novel genetic or epigenetic clues linked to the primary oligodendrogliopathy in MSA [199] may be crucial for understanding the pathogenesis of this disorder.

Therefore, MSA could be considered a disease that is related to a complex genetic and non-genetic interplay. Interaction of those factors could also contribute to the phenotypic variability of MSA (cerebellar or parkinsonian MSA in various combinations) among different populations, as it was discussed by Ozawa and colleagues [200]. How and whether certain risk factors contribute to MSA remains unclear, but the investigation of those factors is a key topic for promising future research initiatives. Furthermore, epigenetic disease markers may prove a potential role as novel biomarkers in the early diagnosis of MSA.

  1. Graham JG, Oppenheimer DR. Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 1969;32:28-34.
    Pubmed
  2. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 1997;49:1284-1288.
    Pubmed
  3. Wenning GK, Colosimo C, Geser F, Poewe W. Multiple system atrophy. Lancet Neurol 2004;3:93-103.
    Pubmed
  4. Wüllner U, Schmitz-Hubsch T, Abele M, Antony G, Bauer P, Eggert K. Features of probable multiple system atrophy patients identified among 4770 patients with parkinsonism enrolled in the multicentre registry of the German Competence Network on Parkinson's disease. J Neural Transm 2007;114:1161-1165.
    Pubmed
  5. Schrag A, Wenning GK, Quinn N, Ben-Shlomo Y. Survival in multiple system atrophy. Mov Disord 2008;23:294-296.
    Pubmed
  6. Quinn N. Multiple system atrophy--the nature of the beast. J Neurol Neurosurg Psychiatry 1989;:78-89.
    Pubmed
  7. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 1989;94:79-100.
    Pubmed
  8. Stefanova N, Bücke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol 2009;8:1172-1178.
    Pubmed
  9. Ishizawa K, Komori T, Sasaki S, Arai N, Mizutani T, Hirose T. Microglial activation parallels system degeneration in multiple system atrophy. J Neuropathol Exp Neurol 2004;63:43-52.
    Pubmed
  10. Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, Healy DG, Wood NW, Lees AJ, Holton JL, Revesz T. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 2004;127:2657-2671.
    Pubmed
  11. Gerhard A, Banati RB, Goerres GB, Cagnin A, Myers R, Gunn RN, Turkheimer F, Good CD, Mathias CJ, Quinn N, Schwarz J, Brooks DJ. [11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology 2003;61:686-689.
    Pubmed
  12. Jellinger KA, Seppi K, Wenning GK. Mov DGrading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov Disord 2005;20:S29-S36.
    Pubmed
  13. Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett 1998;251:205-208.
    Pubmed
  14. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H. Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 1998;249:180-182.
    Pubmed
  15. Okochi M, Walter J, Koyama A, Nakajo S, Baba M, Iwatsubo T, Meijer L, Kahle PJ, Haass C. Constitutive phosphorylation of the Parkinson's disease associated alpha-synuclein. J Biol Chem 2000;275:390-397.
    Pubmed
  16. Giasson BI, Mabon ME, Duda JE, Montine TJ, Robertson D, Hurtig HI, Lee VM, Trojanowski JQ. Tau and 14-3-3 in glial cytoplasmic inclusions of multiple system atrophy. Acta Neuropathol 2003;106:243-250.
    Pubmed
  17. Tang XM, Strocchi P, Cambi F. Changes in the activity of cdk2 and cdk5 accompany differentiation of rat primary oligodendrocytes. J Cell Biochem 1998;68:128-137.
    Pubmed
  18. Griffin SV, Hiromura K, Pippin J, Petermann AT, Blonski MJ, Krofft R, Takahashi S, Kulkarni AB, Shankland SJ. Cyclin-dependent kinase 5 is a regulator of podocyte differentiation, proliferation, and morphology. Am J Pathol 2004;165:1175-1185.
    Pubmed
  19. Abe H, Yagishita S, Amano N, Iwabuchi K, Hasegawa K, Kowa K. Argyrophilic glial intracytoplasmic inclusions in multiple system atrophy: immunocytochemical and ultrastructural study. Acta Neuropathol 1992;84:273-277.
    Pubmed
  20. Arai N, Nishimura M, Oda M, Morimatsu Y, Ohe R, Nagatomo H. Immunohistochemical expression of microtubule-associated protein 5 (MAP5) in glial cells in multiple system atrophy. J Neurol Sci 1992;109:102-106.
    Pubmed
  21. Song YJ, Lundvig DM, Huang Y, Gai WP, Blumbergs PC, Højrup P, Otzen D, Halliday GM, Jensen PH. p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 2007;171:1291-1303.
    Pubmed
  22. Kawamoto Y, Akiguchi I, Shirakashi Y, Honjo Y, Tomimoto H, Takahashi R, Budka H. Accumulation of Hsc70 and Hsp70 in glial cytoplasmic inclusions in patients with multiple system atrophy. Brain Res 2007;1136:219-227.
    Pubmed
  23. Huang Y, Song YJ, Murphy K, Holton JL, Lashley T, Revesz T, Gai WP, Halliday GM. LRRK2 and parkin immunoreactivity in multiple system atrophy inclusions. Acta Neuropathol 2008;116:639-646.
    Pubmed
  24. Fellner L, Jellinger KA, Wenning GK, Stefanova N. Glial dysfunction in the pathogenesis of alpha-synucleinopathies: emerging concepts. Acta Neuropathol 2011;121:675-693.
    Pubmed
  25. Tanji K, Odagiri S, Maruyama A, Mori F, Kakita A, Takahashi H, Wakabayashi K. Alteration of autophagosomal proteins in the brain of multiple system atrophy. Neurobiol Dis 2012;49C:190-198.
    Pubmed
  26. Scholz SW, Houlden H, Schulte C, Sharma M, Li A, Berg D, Melchers A, Paudel R, Gibbs JR, Simon-Sanchez J, Paisan-Ruiz C, Bras J, Ding J, Chen H, Traynor BJ, Arepalli S, Zonozi RR, Revesz T, Holton J, Wood N, Lees A, Oertel W, Wüllner U, Goldwurm S, Pellecchia MT, Illig T, Riess O, Fernandez HH, Rodriguez RL, Okun MS, Poewe W, Wenning GK, Hardy JA, Singleton AB, Del Sorbo F, Schneider S, Bhatia KP, Gasser T. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 2009;65:610-614.
    Pubmed
  27. Wenning GK, Wagner S, Daniel S, Quinn NP. Multiple system atrophy: sporadic or familial?. Lancet 1993;342:681.
  28. Brown RC, Lockwood AH, Sonawane BR. Neurodegenerative diseases: an overview of environmental risk factors. Environ Health Perspect 2005;113:1250-1256.
    Pubmed
  29. Hara K, Momose Y, Tokiguchi S, Shimohata M, Terajima K, Onodera O, Kakita A, Yamada M, Takahashi H, Hirasawa M, Mizuno Y, Ogata K, Goto J, Kanazawa I, Nishizawa M, Tsuji S. Multiplex families with multiple system atrophy. Arch Neurol 2007;64:545-551.
    Pubmed
  30. Wüllner U, Schmitt I, Kammal M, Kretzschmar HA, Neumann M. Definite multiple system atrophy in a German family. J Neurol Neurosurg Psychiatry 2009;80:449-450.
    Pubmed
  31. Hohler AD, Singh VJ. Probable hereditary multiple system atrophy-autonomic (MSA-A) in a family in the United States. J Clin Neurosci 2012;19:479-480.
    Pubmed
  32. Soma H, Yabe I, Takei A, Fujiki N, Yanagihara T, Sasaki H. Heredity in multiple system atrophy. J Neurol Sci 2006;240:107-110.
    Pubmed
  33. Wüllner U, Abele M, Schmitz-Huebsch T, Wilhelm K, Benecke R, Deuschl G, Klockgether T. Probable multiple system atrophy in a German family. J Neurol Neurosurg Psychiatry 2004;75:924-925.
    Pubmed
  34. Itoh K, Kasai T, Tsuji Y, Saito K, Mizuta I, Harada Y, Sudoh S, Mizuno T, Nakagawa M, Fushiki S. Definite familial multiple system atrophy with unknown genetics. Neuropathology 2014;34:309-313.
    Pubmed
  35. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045-2047.
    Pubmed
  36. Papadimitriou A, Comi GP, Hadjigeorgiou GM, Bordoni A, Sciacco M, Napoli L, Prelle A, Moggio M, Fagiolari G, Bresolin N, Salani S, Anastasopoulos I, Giassakis G, Divari R, Scarlato G. Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome. Neurology 1998;51:1086-1092.
    Pubmed
  37. Markopoulou K, Wszolek ZK, Pfeiffer RF. A Greek-American kindred with autosomal dominant, levodopa-responsive parkinsonism and anticipation. Ann Neurol 1995;38:373-378.
    Pubmed
  38. Markopoulou K, Wszolek ZK, Pfeiffer RF, Chase BA. Reduced expression of the G209A alpha-synuclein allele in familial Parkinsonism. Ann Neurol 1999;46:374-381.
    Pubmed
  39. Papapetropoulos S, Paschalis C, Athanassiadou A, Papadimitriou A, Ellul J, Polymeropoulos MH, Papapetropoulos T. Clinical phenotype in patients with alpha-synuclein Parkinson's disease living in Greece in comparison with patients with sporadic Parkinson's disease. J Neurol Neurosurg Psychiatry 2001;70:662-665.
    Pubmed
  40. Spira PJ, Sharpe DM, Halliday G, Cavanagh J, Nicholson GA. Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation. Ann Neurol 2001;49:313-319.
    Pubmed
  41. Bostantjopoulou S, Katsarou Z, Papadimitriou A, Veletza V, Hatzigeorgiou G, Lees A. Clinical features of parkinsonian patients with the alpha-synuclein (G209A) mutation. Mov Disord 2001;16:1007-1013.
    Pubmed
  42. Chan P, Tanner CM, Jiang X, Langston JW. Failure to find the alpha-synuclein gene missense mutation (G209A) in 100 patients with younger onset Parkinson's disease. Neurology 1998;50:513-514.
    Pubmed
  43. Wang WW, Khajavi M, Patel BJ, Beach J, Jankovic J, Ashizawa T. The G209A mutation in the alpha-synuclein gene is not detected in familial cases of Parkinson disease in non-Greek and/or Italian populations. Arch Neurol 1998;55:1521-1523.
    Pubmed
  44. Lin JJ, Yueh KC, Chang DC, Lin SZ. Absence of G209A and G88C mutations in the alpha-synuclein gene of Parkinson's disease in a Chinese population. Eur Neurol 1999;42:217-220.
    Pubmed
  45. Teive HA, Raskin S, Iwamoto FM, Germiniani FM, Baran MH, Werneck LC, Allan N, Quagliato E, Leroy E, Ide SE, Polymeropoulos MH. The G209A mutation in the alpha-synuclein gene in Brazilian families with Parkinson's disease. Arq Neuropsiquiatr 2001;59:722-724.
    Pubmed
  46. Papapetropoulos S, Paschalis C, Ellul J, Papapetropoulos T, Athanassiadou A. Survival duration of Parkinson's disease patients living in Greece who carry the G209A alpha-synuclein mutation. Mov Disord 2002;17:847-848.
    Pubmed
  47. Papapetropoulos S, Ellul J, Paschalis C, Athanassiadou A, Papadimitriou A, Papapetropoulos T. Clinical characteristics of the alpha-synuclein mutation (G209A)-associated Parkinson's disease in comparison with other forms of familial Parkinson's disease in Greece. Eur J Neurol 2003;10:281-286.
    Pubmed
  48. Orth M, Tabrizi SJ, Tomlinson C, Messmer K, Korlipara LV, Schapira AH, Cooper JM. G209A mutant alpha synuclein expression specifically enhances dopamine induced oxidative damage. Neurochem Int 2004;45:669-676.
    Pubmed
  49. Bostantjopoulou S, Katsarou Z, Gerasimou G, Costa DC, Gotzamani-Psarrakou A. (123)I-FP-CIT SPET striatal uptake in parkinsonian patients with the alpha-synuclein (G209A) mutation A. Hell J Nucl Med 2008;11:157-159.
    Pubmed
  50. Krüger R, Kuhn W, Leenders KL, Sprengelmeyer R, Müller T, Woitalla D, Portman AT, Maguire RP, Veenma L, Schröder U, Schöls L, Epplen JT, Riess O, Przuntek H. Familial parkinsonism with synuclein pathology: clinical and PET studies of A30P mutation carriers. Neurology 2001;56:1355-1362.
    Pubmed
  51. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 1998;18:106-108.
    Pubmed
  52. Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Muñoz DG, de Yebenes JG. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004;55:164-173.
    Pubmed
  53. Conway KA, Harper JD, Lansbury PT. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 1998;4:1318-1320.
    Pubmed
  54. Pandey N, Schmidt RE, Galvin JE. The alpha-synuclein mutation E46K promotes aggregation in cultured cells. Exp Neurol 2006;197:515-520.
    Pubmed
  55. Narhi L, Wood SJ, Steavenson S, Jiang Y, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P, Louis JC, Wypych J, Biere AL, Citron M. Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation. J Biol Chem 1999;274:9843-9846.
    Pubmed
  56. Hoffman-Zacharska D, Koziorowski D, Ross OA, Milewski M, Poznański J, Jurek M, Wszolek ZK, Soto-Ortolaza A, Sławek J, Janik P, Jamrozik Z, Potulska-Chromik A, Jasińska-Myga B, Opala G, Krygowska-Wajs A, Czyżewski K, Dickson DW, Bal J, Friedman A. Novel A18T and pA29S substitutions in alpha-synuclein may be associated with sporadic Parkinson's disease. Parkinsonism Relat Disord 2013;19:1057-1060.
    Pubmed
  57. Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B, Weir D, Thompson C, Szu-Tu C, Trinh J, Aasly JO, Rajput A, Rajput AH, Jon Stoessl A, Farrer MJ. Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease. Mov Disord 2013;28:811-813.
    Pubmed
  58. Proukakis C, Dudzik CG, Brier T, MacKay DS, Cooper JM, Millhauser GL, Houlden H, Schapira AH. A novel α-synuclein missense mutation in Parkinson disease. Neurology 2013;80:1062-1064.
    Pubmed
  59. Rutherford NJ, Moore BD, Golde TE, Giasson BI. Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein. J Neurochem 2014
  60. Khalaf O, Fauvet B, Oueslati A, Dikiy I, Mahul-Mellier AL, Ruggeri FS, Mbefo MK, Vercruysse F, Dietler G, Lee SJ, Eliezer D, Lashuel HA. The H50Q mutation enhances alpha-synuclein aggregation, secretion and toxicity. J Biol Chem 2014;289:21856-21876.
    Pubmed
  61. Ghosh D, Mondal M, Mohite GM, Singh PK, Ranjan P, Anoop A, Ghosh S, Jha NN, Kumar A, Maji SK. The Parkinson's disease-associated H50Q mutation accelerates alpha-Synuclein aggregation in vitro. Biochemistry 2013;52:6925-6927.
    Pubmed
  62. Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P, Proukakis C, Quinn N, Lees AJ, Hardy J, Revesz T, Houlden H, Holton JL. α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy?. Acta Neuropathol 2013;125:753-769.
    Pubmed
  63. Fares MB, Ait-Bouziad N, Dikiy I, Mbefo MK, Jovičič A, Kiely A, Holton JL, Lee SJ, Gitler AD, Eliezer D, Lashuel HA. The novel Parkinson's disease linked mutation G51D attenuates in vitro aggregation and membrane binding of alpha-synuclein, and enhances its secretion and nuclear localization in cells. Hum Mol Genet 2014;23:4491-4509.
    Pubmed
  64. Ozawa T, Takano H, Onodera O, Kobayashi H, Ikeuchi T, Koide R, Okuizumi K, Shimohata T, Wakabayashi K, Takahashi H, Tsuji S. No mutation in the entire coding region of the alpha-synuclein gene in pathologically confirmed cases of multiple system atrophy. Neurosci Lett 1999;270:110-112.
    Pubmed
  65. Morris HR, Vaughan JR, Datta SR, Bandopadhyay R, Rohan De Silva HA, Schrag A, Cairns NJ, Burn D, Nath U, Lantos PL, Daniel S, Lees AJ, Quinn NP, Wood NW. Multiple system atrophy/progressive supranuclear palsy: alpha-Synuclein, synphilin, tau, and APOE. Neurology 2000;55:1918-1920.
    Pubmed
  66. Lincoln SJ, Ross OA, Milkovic NM, Dickson DW, Rajput A, Robinson CA, Papapetropoulos S, Mash DC, Farrer MJ. Quantitative PCR-based screening of alpha-synuclein multiplication in multiple system atrophy. Parkinsonism Relat Disord 2007;13:340-342.
    Pubmed
  67. Ozawa T, Healy DG, Abou-Sleiman PM, Ahmadi KR, Quinn N, Lees AJ, Shaw K, Wullner U, Berciano J, Moller JC, Kamm C, Burk K, Josephs KA, Barone P, Tolosa E, Goldstein DB, Wenning G, Geser F, Holton JL, Gasser T, Revesz T, Wood NW, European MSA study group. The alpha-synuclein gene in multiple system atrophy. J Neurol Neurosurg Psychiatry 2006;77:464-467.
    Pubmed
  68. Markopoulou K, Dickson DW, McComb RD, Wszolek ZK, Katechalidou L, Avery L, Stansbury MS, Chase BA. Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson's disease. Variability in familial Parkinson's disease. Acta Neuropathol 2008;116:25-35.
    Pubmed
  69. Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH, Hardy J, Dickson DW. Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol 2000;99:663-672.
    Pubmed
  70. Pasanen P, Myllykangas L, Siitonen M, Raunio A, Kaakkola S, Lyytinen J, Tienari PJ, Pöyhönen M, Paetau A. A novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology. Neurobiol Aging 2014;35:2180.e1-2180.e5.
    Pubmed
  71. Fuchs J, Nilsson C, Kachergus J, Munz M, Larsson EM, Schüle B, Langston JW, Middleton FA, Ross OA, Hulihan M, Gasser T, Farrer MJ. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 2007;68:916-922.
    Pubmed
  72. Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Krüger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009;41:1308-1312.
    Pubmed
  73. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 2009;41:1303-1307.
    Pubmed
  74. Ross OA, Vilariño-Güell C, Wszolek ZK, Farrer MJ, Dickson DW. Reply to: SNCA variants are associated with increased risk of multiple system atrophy. Ann Neurol 2010;67:414-415.
    Pubmed
  75. Al-Chalabi A, Dürr A, Wood NW, Parkinson MH, Camuzat A, Hulot JS, Morrison KE, Renton A, Sussmuth SD, Landwehrmeyer BG, Ludolph A, Agid Y, Brice A, Leigh PN, Bensimon G. Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy. PLoS One 2009;4:e7114.
    Pubmed
  76. Yun JY, Lee WW, Lee JY, Kim HJ, Park SS, Jeon BS. SNCA variants and multiple system atrophy. Ann Neurol 2010;67:554-555.
    Pubmed
  77. Quinzii C, Naini A, Salviati L, Trevisson E, Navas P, Dimauro S, Hirano M. A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 2006;78:345-349.
    Pubmed
  78. Multiple-System Atrophy Research Collaboration. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med 2013;369:233-244.
    Pubmed
  79. Jeon BS, Farrer MJ, Bortnick SF, Korean Canadian Alliance on Parkinson's Disease and Related Disorders. Mutant COQ2 in multiple-system atrophy. N Engl J Med 2014;371:80.
    Pubmed
  80. López-Martín JM, Salviati L, Trevisson E, Montini G, DiMauro S, Quinzii C, Hirano M, Rodriguez-Hernandez A, Cordero MD, Sánchez-Alcázar JA, Santos-Ocaña C, Navas P. Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis. Hum Mol Genet 2007;16:1091-1097.
    Pubmed
  81. Sharma M, Wenning G, Krüger R, European Multiple-System Atrophy Study Group (EMSA-SG). Mutant COQ2 in multiple-system atrophy. N Engl J Med 2014;371:80-81.
    Pubmed
  82. Schottlaender LV, Houlden H, Multiple-System Atrophy (MSA) Brain Bank Collaboration. Mutant COQ2 in multiple-system atrophy. N Engl J Med 2014;371:81.
    Pubmed
  83. Quinzii CM, Hirano M, DiMauro S. Mutant COQ2 in multiple-system atrophy. N Engl J Med 2014;371:81-82.
    Pubmed
  84. Bleasel JM, Wong JH, Halliday GM, Kim WS. Lipid dysfunction and pathogenesis of multiple system atrophy. Acta Neuropathol Commun 2014;2:15.
    Pubmed
  85. Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 2004;3:291-304.
    Pubmed
  86. Gilman S, Sima AA, Junck L, Kluin KJ, Koeppe RA, Lohman ME, Little R. Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol 1996;39:241-255.
    Pubmed
  87. Nirenberg MJ, Libien J, Vonsattel JP, Fahn S. Multiple system atrophy in a patient with the spinocerebellar ataxia 3 gene mutation. Mov Disord 2007;22:251-254.
    Pubmed
  88. Khan NL, Giunti P, Sweeney MG, Scherfler C, Brien MO, Piccini P, Wood NW, Lees AJ. Parkinsonism and nigrostriatal dysfunction are associated with spinocerebellar ataxia type 6 (SCA6). Mov Disord 2005;20:1115-1119.
    Pubmed
  89. Lee WY, Jin DK, Oh MR, Lee JE, Song SM, Lee EA, Kim GM, Chung JS, Lee KH. Frequency analysis and clinical characterization of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Korean patients. Arch Neurol 2003;60:858-863.
    Pubmed
  90. Kamm C, Healy DG, Quinn NP, Wüllner U, Moller JC, Schols L, Geser F, Burk K, Børglum AD, Pellecchia MT, Tolosa E, del Sorbo F, Nilsson C, Bandmann O, Sharma M, Mayer P, Gasteiger M, Haworth A, Ozawa T, Lees AJ, Short J, Giunti P, Holinski-Feder E, Illig T, Wichmann HE, Wenning GK, Wood NW, Gasser T, European Multiple System Atrophy Study Group. The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group. Brain 2005;128:1855-1860.
    Pubmed
  91. Probst-Cousin S, Acker T, Epplen JT, Bergmann M, Plate KH, Neundörfer B, Heuss D. Spinocerebellar ataxia type 2 with glial cell cytoplasmic inclusions. J Neurol Neurosurg Psychiatry 2004;75:503-505.
    Pubmed
  92. Berciano J, Ferrer I. Glial cell cytoplasmic inclusions in SCA2 do not express alpha-synuclein. J Neurol 2005;252:742-744.
    Pubmed
  93. Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, Wenning GK. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999;163:94-98.
    Pubmed
  94. Bandmann O, Sweeney MG, Daniel SE, Wenning GK, Quinn N, Marsden CD, Wood NW. Multiple-system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration. Neurology 1997;49:1598-1604.
    Pubmed
  95. Kim JY, Kim SY, Kim JM, Kim YK, Yoon KY, Kim JY, Lee BC, Kim JS, Paek SH, Park SS, Kim SE, Jeon BS. Spinocerebellar ataxia type 17 mutation as a causative and susceptibility gene in parkinsonism. Neurology 2009;72:1385-1389.
    Pubmed
  96. Lin IS, Wu RM, Lee-Chen GJ, Shan DE, Gwinn-Hardy K. The SCA17 phenotype can include features of MSA-C, PSP and cognitive impairment. Parkinsonism Relat Disord 2007;13:246-249.
    Pubmed
  97. Factor SA, Qian J, Lava NS, Hubbard JD, Payami H. False-positive SCA8 gene test in a patient with pathologically proven multiple system atrophy. Ann Neurol 2005;57:462-463.
    Pubmed
  98. Furiya Y, Hirano M, Kurumatani N, Nakamuro T, Matsumura R, Futamura N, Ueno S. Alpha-1-antichymotrypsin gene polymorphism and susceptibility to multiple system atrophy (MSA). Brain Res Mol Brain Res 2005;138:178-181.
    Pubmed
  99. Kremer EJ, Pritchard M, Lynch M, Yu S, Holman K, Baker E, Warren ST, Schlessinger D, Sutherland GR, Richards RI. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 1991;252:1711-1714.
    Pubmed
  100. Leehey MA, Munhoz RP, Lang AE, Brunberg JA, Grigsby J, Greco C, Jacquemont S, Tassone F, Lozano AM, Hagerman PJ, Hagerman RJ. The fragile X premutation presenting as essential tremor. Arch Neurol 2003;60:117-121.
    Pubmed
  101. Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA. Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 2007;6:45-55.
    Pubmed
  102. Yabe I, Soma H, Takei A, Fujik N, Sasaki H. No association between FMR1 premutations and multiple system atrophy. J Neurol 2004;251:1411-1412.
    Pubmed
  103. Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 2010;31:763-780.
    Pubmed
  104. Hatano T, Kubo S, Sato S, Hattori N. Pathogenesis of familial Parkinson's disease: new insights based on monogenic forms of Parkinson's disease. J Neurochem 2009;111:1075-1093.
    Pubmed
  105. Brooks JA, Houlden H, Melchers A, Islam AJ, Ding J, Li A, Paudel R, Revesz T, Holton JL, Wood N, Lees A, Singleton AB, Scholz SW. Mutational analysis of parkin and PINK1 in multiple system atrophy. Neurobiol Aging 2011;32:548.e5-548.e7.
    Pubmed
  106. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998;43:815-825.
    Pubmed
  107. Abraham R, Sims R, Carroll L, Hollingworth P, O'Donovan MC, Williams J, Owen MJ. An association study of common variation at the MAPT locus with late-onset Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet 2009;150B:1152-1155.
    Pubmed
  108. Wider C, Vilariño-Güell C, Jasinska-Myga B, Heckman MG, Soto-Ortolaza AI, Cobb SA, Aasly JO, Gibson JM, Lynch T, Uitti RJ, Wszolek ZK, Farrer MJ, Ross OA. Association of the MAPT locus with Parkinson's disease. Eur J Neurol 2010;17:483-486.
    Pubmed
  109. Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab 2004;81:70-73.
    Pubmed
  110. Sidransky E. Heterozygosity for a Mendelian disorder as a risk factor for complex disease. Clin Genet 2006;70:275-282.
    Pubmed
  111. Segarane B, Li A, Paudel R, Scholz S, Neumann J, Lees A, Revesz T, Hardy J, Mathias CJ, Wood NW, Holton J, Houlden H. Glucocerebrosidase mutations in 108 neuropathologically confirmed cases of multiple system atrophy. Neurology 2009;72:1185-1186.
    Pubmed
  112. Ozelius LJ, Foroud T, May S, Senthil G, Sandroni P, Low PA, Reich S, Colcher A, Stern MB, Ondo WG, Jankovic J, Huang N, Tanner CM, Novak P, Gilman S, Marshall FJ, Wooten GF, Chelimsky TC, Shults CW, North American Multiple System Atrophy Study Group. G2019S mutation in the leucine-rich repeat kinase 2 gene is not associated with multiple system atrophy. Mov Disord 2007;22:546-549.
    Pubmed
  113. Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, Litvan I, Gordon MF, Wszolek ZK, Farrer MJ, Dickson DW. Lrrk2 and Lewy body disease. Ann Neurol 2006;59:388-393.
    Pubmed
  114. Tan EK, Skipper L, Chua E, Wong MC, Pavanni R, Bonnard C, Kolatkar P, Liu JJ. Analysis of 14 LRRK2 mutations in Parkinson's plus syndromes and late-onset Parkinson's disease. Mov Disord 2006;21:997-1001.
    Pubmed
  115. Ozawa T. Pathology and genetics of multiple system atrophy: an approach to determining genetic susceptibility spectrum. Acta Neuropathol 2006;112:531-538.
    Pubmed
  116. Cairns NJ, Atkinson PF, Kovács T, Lees AJ, Daniel SE, Lantos PL. Apolipoprotein E e4 allele frequency in patients with multiple system atrophy. Neurosci Lett 1997;221:161-164.
    Pubmed
  117. Morris HR, Schrag A, Nath U, Burn D, Quinn NP, Daniel S, Wood NW, Lees AJ. Effect of ApoE and tau on age of onset of progressive supranuclear palsy and multiple system atrophy. Neurosci Lett 2001;312:118-120.
    Pubmed
  118. Yu CE, Bird TD, Bekris LM, Montine TJ, Leverenz JB, Steinbart E, Galloway NM, Feldman H, Woltjer R, Miller CA, Wood EM, Grossman M, McCluskey L, Clark CM, Neumann M, Danek A, Galasko DR, Arnold SE, Chen-Plotkin A, Karydas A, Miller BL, Trojanowski JQ, Lee VM, Schellenberg GD, Van Deerlin VM. The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol 2010;67:161-170.
    Pubmed
  119. Cho S, Kim CH, Cubells JF, Zabetian CP, Hwang DY, Kim JW, Cohen BM, Biaggioni I, Robertson D, Kim KS. Variations in the dopamine beta-hydroxylase gene are not associated with the autonomic disorders, pure autonomic failure, or multiple system atrophy. Am J Med Genet A 2003;120A:234-236.
    Pubmed
  120. Bandmann O, Wenning GK, Quinn NP, Harding AE. Arg296 to Cys296 polymorphism in exon 6 of cytochrome P-450-2D6 (CYP2D6) is not associated with multiple system atrophy. J Neurol Neurosurg Psychiatry 1995;59:557.
    Pubmed
  121. Iwahashi K, Miyatake R, Tsuneoka Y, Matsuo Y, Ichikawa Y, Hosokawa K, Sato K, Hayabara T. A novel cytochrome P-450IID6 (CYPIID6) mutant gene associated with multiple system atrophy. J Neurol Neurosurg Psychiatry 1995;58:263-264.
    Pubmed
  122. Planté-Bordeneuve V, Bandmann O, Wenning G, Quinn NP, Daniel SE, Harding AE. CYP2D6-debrisoquine hydroxylase gene polymorphism in multiple system atrophy. Mov Disord 1995;10:277-278.
    Pubmed
  123. Jamrozik Z, Berdynski M, Zekanowski C, Baranczyk-Kuzma A, Slawek J, Kuzma-Kozakiewicz M, Maruszak A, Kwiecinski H. Analysis of PITX3 gene in patients with multisystem atrophy, progressive supranuclear palsy and corticobasal degeneration. Ann Clin Lab Sci 2013;43:151-153.
    Pubmed
  124. Guo XY, Chen YP, Song W, Zhao B, Cao B, Wei QQ, Ou RW, Yang Y, Yuan LX, Shang HF. An association analysis of the rs1572931 polymorphism of the RAB7L1 gene in Parkinson's disease, amyotrophic lateral sclerosis and multiple system atrophy in China. Eur J Neurol 2014;21:1337-1343.
    Pubmed
  125. Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease--a double-edged sword. Neuron 2002;35:419-432.
    Pubmed
  126. Combarros O, Infante J, Llorca J, Berciano J. Interleukin-1A (-889) genetic polymorphism increases the risk of multiple system atrophy. Mov Disord 2003;18:1385-1386.
    Pubmed
  127. Nishimura M, Kawakami H, Komure O, Maruyama H, Morino H, Izumi Y, Nakamura S, Kaji R, Kuno S. Contribution of the interleukin-1beta gene polymorphism in multiple system atrophy. Mov Disord 2002;17:808-811.
    Pubmed
  128. Infante J, Llorca J, Berciano J, Combarros O. Interleukin-8, intercellular adhesion molecule-1 and tumour necrosis factor-alpha gene polymorphisms and the risk for multiple system atrophy. J Neurol Sci 2005;228:11-13.
    Pubmed
  129. Nishimura M, Kuno S, Kaji R, Kawakami H. Influence of a tumor necrosis factor gene polymorphism in Japanese patients with multiple system atrophy. Neurosci Lett 2005;374:218-221.
    Pubmed
  130. Soma H, Yabe I, Takei A, Fujiki N, Yanagihara T, Sasaki H. Associations between multiple system atrophy and polymorphisms of SLC1A4, SQSTM1, and EIF4EBP1 genes. Mov Disord 2008;23:1161-1167.
    Pubmed
  131. Schmitt I, Wüllner U, Healy DG, Wood NW, Kölsch H, Heun R. The ADH1C stop mutation in multiple system atrophy patients and healthy probands in the United Kingdom and Germany. Mov Disord 2006;21:2034.
    Pubmed
  132. Kim HS, Lee MS. Frequencies of single nucleotide polymorphism in alcohol dehydrogenase7 gene in patients with multiple system atrophy and controls. Mov Disord 2003;18:1065-1067.
    Pubmed
  133. Annic A, Devos D, Destée A, Defebvre L, Lacour A, Hurtevent JF, Stojkovic T. Early dopasensitive Parkinsonism related to myotonic dystrophy type 2. Mov Disord 2008;23:2100-2101.
    Pubmed
  134. Lim SY, Wadia P, Wenning GK, Lang AE. Clinically probable multiple system atrophy with predominant parkinsonism associated with myotonic dystrophy type 2. Mov Disord 2009;24:1407-1409.
    Pubmed
  135. Goedert M, Clavaguera F, Tolnay M. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 2010;33:317-325.
    Pubmed
  136. Shibao C, Garland EM, Gamboa A, Vnencak-Jones CL, Van Woeltz M, Haines JL, Yu C, Biaggioni I. PRNP M129V homozygosity in multiple system atrophy vs. Parkinson's disease. Clin Auton Res 2008;18:13-19.
    Pubmed
  137. Goldman JS, Quinzii C, Dunning-Broadbent J, Waters C, Mitsumoto H, Brannagan TH, Cosentino S, Huey ED, Nagy P, Kuo SH. Multiple system atrophy and amyotrophic lateral sclerosis in a family with hexanucleotide repeat expansions in C9orf72. JAMA Neurol 2014;71:771-774.
    Pubmed
  138. Sasaki H, Emi M, Iijima H, Ito N, Sato H, Yabe I, Kato T, Utsumi J, Matsubara K. Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy. Mol Brain 2011;4:24.
    Pubmed
  139. Nakamura T, Muraoka S, Sanokawa R, Mori N. N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling. J Biol Chem 1998;273:6960-6967.
    Pubmed
  140. Sakai R, Henderson JT, O'Bryan JP, Elia AJ, Saxton TM, Pawson T. The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons. Neuron 2000;28:819-833.
    Pubmed
  141. Ferguson MC, Garland EM, Hedges L, Womack-Nunley B, Hamid R, Phillips JA, Shibao CA, Raj SR, Biaggioni I, Robertson D. SHC2 gene copy number in multiple system atrophy (MSA). Clin Auton Res 2014;24:25-30.
    Pubmed
  142. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010;28:1057-1068.
    Pubmed
  143. Halusková J. Epigenetic studies in human diseases. Folia Biol (Praha) 2010;56:83-96.
    Pubmed
  144. Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell 2014;54:716-727.
    Pubmed
  145. Turunen MP, Aavik E, Ylä-Herttuala S. Epigenetics and atherosclerosis. Biochim Biophys Acta 2009;1790:886-891.
    Pubmed
  146. Abi Khalil C. The emerging role of epigenetics in cardiovascular disease. Ther Adv Chronic Dis 2014;5:178-187.
    Pubmed
  147. Hewagama A, Richardson B. The genetics and epigenetics of autoimmune diseases. J Autoimmun 2009;33:3-11.
    Pubmed
  148. Wang J, Wu Z, Li D, Li N, Dindot SV, Satterfield MC, Bazer FW, Wu G. Nutrition, epigenetics, and metabolic syndrome. Antioxid Redox Signal 2012;17:282-301.
    Pubmed
  149. Vickers MH. Early life nutrition, epigenetics and programming of later life disease. Nutrients 2014;6:2165-2178.
    Pubmed
  150. Tawil R, van der Maarel SM, Tapscott SJ. Facioscapulohumeral dystrophy: the path to consensus on pathophysiology. Skelet Muscle 2014;4:12.
    Pubmed
  151. Day JJ, Sweatt JD. Cognitive neuroepigenetics: a role for epigenetic mechanisms in learning and memory. Neurobiol Learn Mem 2011;96:2-12.
    Pubmed
  152. Gräff J, Mansuy IM. Epigenetic codes in cognition and behaviour. Behav Brain Res 2008;192:70-87.
    Pubmed
  153. Modgil S, Lahiri DK, Sharma VL, Anand A. Role of early life exposure and environment on neurodegeneration: implications on brain disorders. Transl Neurodegener 2014;3:9.
    Pubmed
  154. Kanthasamy A, Jin H, Anantharam V, Sondarva G, Rangasamy V, Rana A, Kanthasamy A. Emerging neurotoxic mechanisms in environmental factors-induced neurodegeneration. Neurotoxicology 2012;33:833-837.
    Pubmed
  155. Munger KL, Ascherio A. Risk factors in the development of multiple sclerosis. Expert Rev Clin Immunol 2007;3:739-748.
    Pubmed
  156. Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH. Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 2008;28:3-9.
    Pubmed
  157. Sierksma AS, van den Hove DL, Steinbusch HW, Prickaerts J. Major depression, cognitive dysfunction and Alzheimer's disease: is there a link?. Eur J Pharmacol 2010;626:72-82.
    Pubmed
  158. Lahiri DK, Maloney B, Zawia NH. The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol Psychiatry 2009;14:992-1003.
    Pubmed
  159. Lundberg J, Karimi M, von Gertten C, Holmin S, Ekström TJ, Sandberg-Nordqvist AC. Traumatic brain injury induces relocalization of DNA-methyltransferase 1. Neurosci Lett 2009;457:8-11.
    Pubmed
  160. Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK, Zawia NH. The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci 2005;25:823-829.
    Pubmed
  161. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur J Epidemiol 2011;26:S1-S58.
    Pubmed
  162. Nee LE, Gomez MR, Dambrosia J, Bale S, Eldridge R, Polinsky RJ. Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation. Clin Auton Res 1991;1:9-13.
    Pubmed
  163. Nagai Y, Kitazawa R, Nakagawa M, Komoda M, Kondo T, Haraguchi R, Kitazawa S. Multiple-system atrophy in long-term professional painter: a case report. Case Rep Pathol 2012;2012:613180.
    Pubmed
  164. Hanna PA, Jankovic J, Kirkpatrick JB. Multiple system atrophy: the putative causative role of environmental toxins. Arch Neurol 1999;56:90-94.
    Pubmed
  165. Frumkin H. Multiple system atrophy following chronic carbon disulfide exposure. Environ Health Perspect 1998;106:611-613.
    Pubmed
  166. Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel SE, Lees AJ, Jenner P, Marsden CD. Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain 1991;114:1953-1975.
    Pubmed
  167. Dexter DT, Jenner P, Schapira AH, Marsden CD. Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinsons Disease Research Group. Ann Neurol 1992;32:S94-S100.
    Pubmed
  168. Drayer BP, Olanow W, Burger P, Johnson GA, Herfkens R, Riederer S. Parkinson plus syndrome: diagnosis using high field MR imaging of brain iron. Radiology 1986;159:493-498.
    Pubmed
  169. Alavanja MC, Sandler DP, McMaster SB, Zahm SH, McDonnell CJ, Lynch CF, Pennybacker M, Rothman N, Dosemeci M, Bond AE, Blair A. The Agricultural Health Study. Environ Health Perspect 1996;104:362-369.
    Pubmed
  170. Chrysostome V, Tison F, Yekhlef F, Sourgen C, Baldi I, Dartigues JF. Epidemiology of multiple system atrophy: a prevalence and pilot risk factor study in Aquitaine, France. Neuroepidemiology 2004;23:201-208.
    Pubmed
  171. Vanacore N, Bonifati V, Fabbrini G, Colosimo C, De Michele G, Marconi R, Stocchi F, Nicholl D, Bonuccelli U, De Mari M, Vieregge P, Meco G, ESGAP Consortium. Case-control study of multiple system atrophy. Mov Disord 2005;20:158-163.
    Pubmed
  172. Vidal JS, Vidailhet M, Elbaz A, Derkinderen P, Tzourio C, Alpérovitch A. Risk factors of multiple system atrophy: a case-control study in French patients. Mov Disord 2008;23:797-803.
    Pubmed
  173. Vanacore N, Bonifati V, Fabbrini G, Colosimo C, Marconi R, Nicholl D, Bonuccelli U, Stocchi F, Lamberti P, Volpe G, De Michele G, Iavarone I, Bennett P, Vieregge P, Meco G. Smoking habits in multiple system atrophy and progressive supranuclear palsy. European Study Group on Atypical Parkinsonisms. Neurology 2000;54:114-119.
    Pubmed
  174. Johnsen JA, Miller VT. Tobacco intolerance in multiple system atrophy. Neurology 1986;36:986-988.
    Pubmed
  175. Colosimo C, Inghilleri M. A further case of nicotine sensitivity in multiple system atrophy. Clin Neuropharmacol 2012;35:51-52.
    Pubmed
  176. Wenning GK, Stefanova N. Recent developments in multiple system atrophy. J Neurol 2009;256:1791-1808.
    Pubmed
  177. Wrobel K, Wrobel K, Caruso JA. Epigenetics: an important challenge for ICP-MS in metallomics studies. Anal Bioanal Chem 2009;393:481-486.
    Pubmed
  178. Stover PJ, Caudill MA. Genetic and epigenetic contributions to human nutrition and health: managing genome-diet interactions. J Am Diet Assoc 2008;108:1480-1487.
    Pubmed
  179. Chuang DM, Leng Y, Marinova Z, Kim HJ, Chiu CT. Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 2009;32:591-601.
    Pubmed
  180. Liu J, Casaccia P. Epigenetic regulation of oligodendrocyte identity. Trends Neurosci 2010;33:193-201.
    Pubmed
  181. Trüe O, Matthias P. Interplay between histone deacetylases and autophagy--from cancer therapy to neurodegeneration. Immunol Cell Biol 2012;90:78-84.
    Pubmed
  182. d'Ydewalle C, Bogaert E, Van Den Bosch L. HDAC6 at the intersection of neuroprotection and neurodegeneration. Traffic 2012;13:771-779.
    Pubmed
  183. Miki Y, Mori F, Tanji K, Kakita A, Takahashi H, Wakabayashi K. Accumulation of histone deacetylase 6, an aggresome-related protein, is specific to Lewy bodies and glial cytoplasmic inclusions. Neuropathology 2011;31:561-568.
    Pubmed
  184. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase. Nature 2002;417:455-458.
    Pubmed
  185. Graves P, Zeng Y. Biogenesis of mammalian microRNAs: a global view. Genomics Proteomics Bioinformatics 2012;10:239-245.
    Pubmed
  186. Hong J, Zhang H, Kawase-Koga Y, Sun T. MicroRNA function is required for neurite outgrowth of mature neurons in the mouse postnatal cerebral cortex. Front Cell Neurosci 2013;7:151.
    Pubmed
  187. Ubhi K, Rockenstein E, Kragh C, Inglis C, Spencer B, Michael S, Mante M, Adame A, Galasko D, Masliah E. Widespread microRNA dysregulation in multiple system atrophy - disease-related alteration in miR-96. Eur J Neurosci 2014;39:1026-1041.
    Pubmed
  188. Lee ST, Chu K, Jung KH, Ban JJ, Im WS, Jo HY, Park JH, Lim JY, Shin JW, Moon J, Lee SK, Kim M, Roh JK. Altered Expression of miR-202 in Cerebellum of Multiple-System Atrophy. Mol Neurobiol 2014
  189. Guevara-García M, Gil-del Valle L, Velásquez-Pérez L, García-Rodríguez JC. Oxidative stress as a cofactor in spinocerebellar ataxia type 2. Redox Rep 2012;17:84-89.
    Pubmed
  190. Vallelunga A, Ragusa M, Di Mauro S, Iannitti T, Pilleri M, Biundo R, Weis L, Di Pietro C, De Iuliis A, Nicoletti A, Zappia M, Purrello M, Antonini A. Identification of circulating microRNAs for the differential diagnosis of Parkinson's disease and Multiple System Atrophy. Front Cell Neurosci 2014;8:156.
    Pubmed
  191. Liu DZ, Ander BP, Tian Y, Stamova B, Jickling GC, Davis RR, Sharp FR. Integrated analysis of mRNA and microRNA expression in mature neurons, neural progenitor cells and neuroblastoma cells. Gene 2012;495:120-127.
    Pubmed
  192. Dutta R, Chomyk AM, Chang A, Ribaudo MV, Deckard SA, Doud MK, Edberg DD, Bai B, Li M, Baranzini SE, Fox RJ, Staugaitis SM, Macklin WB, Trapp BD. Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors. Ann Neurol 2013;73:637-645.
    Pubmed
  193. Zhu H, Fan GC. Role of microRNAs in the reperfused myocardium towards post-infarct remodelling. Cardiovasc Res 2012;94:284-292.
    Pubmed
  194. Miñones-Moyano E, Porta S, Escaramís G, Rabionet R, Iraola S, Kagerbauer B, Espinosa-Parrilla Y, Ferrer I, Estivill X, Martí E. MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet 2011;20:3067-3078.
    Pubmed
  195. Gaughwin PM, Ciesla M, Lahiri N, Tabrizi SJ, Brundin P, Björkqvist M. Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease. Hum Mol Genet 2011;20:2225-2237.
    Pubmed
  196. Nunez-Iglesias J, Liu CC, Morgan TE, Finch CE, Zhou XJ. Joint genome-wide profiling of miRNA and mRNA expression in Alzheimer's disease cortex reveals altered miRNA regulation. PLoS One 2010;5:e8898.
    Pubmed
  197. Cogswell JP, Ward J, Taylor IA, Waters M, Shi Y, Cannon B, Kelnar K, Kemppainen J, Brown D, Chen C, Prinjha RK, Richardson JC, Saunders AM, Roses AD, Richards CA. Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 2008;14:27-41.
    Pubmed
  198. Szyf M. Epigenetics, a key for unlocking complex CNS disorders? Therapeutic implications. Eur Neuropsychopharmacol 2014
  199. Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG. Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 2008;64:239-246.
    Pubmed
  200. Ozawa T, Revesz T, Paviour D, Lees AJ, Quinn N, Tada M, Kakita A, Onodera O, Wakabayashi K, Takahashi H, Nishizawa M, Holton JL. Difference in MSA phenotype distribution between populations: genetics or environment?. J Parkinsons Dis 2012;2:7-18.
    Pubmed