Exp Neurobiol 2013; 22(2): 77-83
Published online June 30, 2013
© The Korean Society for Brain and Neural Sciences
Department of Neurology and Movement Disorder Center, College of Medicine,
Seoul National University, Seoul 110-744, Korea
Correspondence to: *To whom correspondence should be addressed.
TEL: 82-2-2072-2278, FAX: 82-2-3672-7553
Although physiological function of alpha-synuclein is not yet clearly understood, accumulating evidence strongly suggests it plays a crucial role in the pathogenesis of Parkinson disease. Pathologically, alpha-synuclein is a major component of Lewy bodies, which is the pathological hallmark of Parkinson disease. Alpha-synuclein pathology is observed in the brainstem nuclei, including the dorsal motor nucleus of the vagus nerve, the locus ceruleus, and the substantia nigra in the early phase of Parkinson disease and it may 'spread' to cerebral cortical areas in the advanced Parkinson disease and appears to have a role in the cognitive decline in Parkinson disease. Recently, it is suggested that alpha-synuclein pathology in Parkinson disease starts in the olfactory bulb or enteric nervous system and then spreads to the brainstem. In accordance with this hypothesis, alpha-synuclein pathology has been found in gastric mucosa and colonic mucosa of patients with Parkinson disease. Genetically,
Keywords: Parkinson disease, alpha-synuclein, neuropathology, genetics
Parkinson's disease (PD) is a movement disorder characterized by tremor at rest, rigidity, and bradykinesia and it is the second most common degenerative disorder followed by Alzheimer's disease. Other motor symptoms manifested by patients with PD include postural instability, stooped posture, freezing of gait, decreased facial expression, hypophonic voice, loss of dexterity, and festinating gait . In addition, many patients have non-motor symptoms including: neuropsychiatric symptoms such as dementia, depression, and anxiety; sleep disorders such as insomnia, excessive daytime sleepiness, and rapid eye movement sleep disorder; autonomic nervous system symptoms such as orthostatic hypotension and micturition disorder; gastrointestinal symptoms such as constipation, difficulty in swallowing, and dyspepsia; and sensory symptoms such olfactory dysfunction, visual abnormality, and pain. The prevalence of PD increases with age and the incidence is reportedly 1-2% over the age of 60 years .
A large number of clinical and basic studies have been performed to elucidate the pathogenesis of PD. The majority of studies have investigated alpha-synuclein. Alpha-synuclein is a 140 amino acid protein that is encoded by the
The importance of alpha-synuclein in PD began to be recognized in the late 1990's. The discovery of two crucial findings during this period triggered the study of alpha-synuclein in PD. The first was a genetic finding. In 1996, Polymeropoulos et al.  reported the A53T mutation of
The aim of this paper is to review the clinical findings of recent studies on PD and alpha-synuclein from the perspectives of physicians. Results from animal studies or basic researches will not be covered in this review as they have been reviewed in recent literature .
In terms of alpha-synuclein pathology, Lewy bodies are found in several regions in the brains of patients with PD. Pathologically, the diagnostic criteria of PD are the death of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. Apart from nigra, alpha-synuclein pathologies are observed in other brainstem nuclei, including the dorsal motor nucleus of vagus (DMX) of medulla, the locus ceruleus in the pons, and the raphe nucleus. Furthermore, alpha-synuclein pathology has been found to exist in the basal forebrain, hippocampus, insular cortex, cingulated gyrus, temporal gyrus, frontal cortex, and other parts of the brain . Most patients with alpha-synuclein pathology in the substantia nigra also have alpha-synuclein pathology in the medulla or pons. On the contrary, some cases with alpha-synuclein pathology in the medulla or pons do not have alpha-synuclein pathology in the midbrain. Based on these findings, Braak et al. proposed the gradual spread of alpha-synuclein pathology . According to their study, the alpha-synuclein pathology of PD begins in the DMX of the medulla and gradually spreads rostrally. Clinical symptoms of PD are manifested as alpha-synuclein pathology reaches substantia nigra and, as the disease progresses, alpha-synuclein pathology is found in the cerebral cortex. This hypothesis has attracted considerable attention and many PD investigators have aligned themselves with this hypothesis. Currently, the theory of Braak et al. has been established as the fundamental hypothesis explaining the pathogenesis and progression of PD. However, some opposing arguments also exist. The more common alpha-synuclein pathology in the medulla or pons than in the midbrain does not necessarily imply transmission of alpha-synuclein pathology from the medulla to the midbrain. Furthermore, studies on the brain of patients with PD showed that more than 15% of brains exhibited the pattern of not following the order of Braak stage progressions. Braak et al. presented dual-hit hypothesis supporting their theory in 2007 , suggesting that the alpha-synuclein pathology of PD is transmitted to the midbrain through two different paths. One path is from the olfactory bulb to the temporal cortex, and the other path is the transmission to DMX through the enteric nervous system. This hypothesis explains that the pathogenesis of PD is initiated by an external factor which directly generates the alpha-synuclein pathology in the olfactory bulb through the nose, or makes contact with the gastrointestinal tract by the swallowing of olfactory mucosal discharge. Autopsy findings of patients with PD have revealed the pathological findings of alpha-synuclein in the enteric nervous system of the stomach and esophagus [11, 12]. According to the outcomes of recent studies, colorectal biopsy revealed the findings of an alpha-synuclein pathology in PD patients .
The most convincing evidence supporting the hypothesis that alpha-synuclein pathology is transmitted through the nervous system was simultaneously reported by two independent research teams in 2008: the brain autopsy of PD patients who received fetal midbrain transplants revealed alpha-synuclein pathology within transplanted neurons [14, 15]. While fetal midbrain transplants had been attempted as a treatment method of PD in the 1990's, in recent years, it is rarely performed due to unclear efficacy, the risk of adverse effects, and ethical problems of obtaining midbrain cells from the fetus. Autopsies were performed in patients who received fetal midbrain transplants and died after 10 years or more. Surprisingly, transplanted cells, which have aged 10 years or slightly more than 10 years, exhibited similar pathological findings of alpha-synuclein shown in host neurons. This finding implies that the alpha-synuclein pathology is transmitted from the surrounding host neurons to the transplanted neurons, as in prion diseases [16, 17]. On the other hand, other interpretations suggested that the occurrence of alpha-synuclein pathology in transplanted neurons is not due to transmission from surrounding host neurons but to the de novo intracellular alpha-synuclein pathology within the transplanted cells exposed to the alpha-synuclein pathology-promoting microenvironment which is shared by host cells. A large number of basic studies have also been carried out, supporting the transmission of alpha-synuclein pathology in PD. Additional studies will be proactively performed to further examine the mechanism of PD based on the new findings in clinical studies.
As stated in the Introduction, many genetic studies have been conducted to clarify the relationship between alpha-synuclein and PD after the discovery of the
More convincing genetic evidence proving the relationship between alpha-synuclein and PD is the multiplication of
Given that alpha-synuclein is the key molecule in the pathogenesis of PD, the presence of the alpha-synuclein pathology in the brain tissues of patients with PD by a genetic abnormality other than
In recent years, many studies have attempted to clarify the relationship between PD and a certain single nucleotide polymorphism (SNP) through a genome-wide association study (GWAS). Numerous GWASs have shown that several SNPs in
Recent studies have presented the relationship between DNA methylation of the
As studies have verified the pathological role of alpha-synuclein in patients with PD, other studies have attempted to apply this pathogenesis in the diagnosis and prognosis of PD.
Until now, no specific diagnostic marker of PD has been identified yet. The diagnosis of PD is still determined solely by the clinical findings. Radiological tests and laboratory findings are used only as supporting tools in diagnosing PD. In these circumstances, the development of a biological marker is crucial for a more precise diagnosis and the prediction of disease before the onset of symptoms. Many studies are currently conducted to find the biomarker in this regard.
Peripheral blood is one of the most accessible biological samples. Several studies have verified an increase in alpha-synuclein in the blood of PD patients compared with normal individuals . However, alpha-synuclein is mostly present in RBCs that contain more than 95% of all alpha-synuclein in the blood . Thus, the alpha-synuclein level measured in the blood sample is inevitably influenced by the minimal difference in the degree of hemolysis and accordingly it is inappropriate to use the blood level of alpha-synuclein for diagnostic purposes. Increases in alpha-synuclein protein and
Some studies have attempted to diagnose PD through alpha-synuclein in other biological samples or tissue specimens. Devic et al.  presented an increase of alpha-synuclein in the saliva of PD patients. In addition, an increase of alpha-synuclein has been found in minor salivary gland biopsies [46, 47], tissues from skin biopsy [48, 49], stomach biopsy , and colonic biopsy , and in fibroblasts obtained from the skin . However, more studies are needed. These findings are anticipated to aid the development of a premortem biomarker crucial in the diagnosis, clarification of the mechanism, and new treatment methods of PD.
Table 1. Genetic etiology of Parkinson disease