Articles

Article

Review Article

Exp Neurobiol 2015; 24(1): 1-7

Published online March 31, 2015

https://doi.org/10.5607/en.2015.24.1.1

© The Korean Society for Brain and Neural Sciences

Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?

Shynrye Lee and Hyung-Jun Kim*

Korea Brain Research Institute, Research Division, Daegu 700-010, Korea

Correspondence to: *To whom correspondence should be addressed.
TEL: 82-70-4496-3296, FAX: 82-53-428-1851
e-mail: kijang1@kbri.re.kr

Received: August 14, 2014; Revised: September 17, 2014; Accepted: September 25, 2014

ALS is a fatal adult-onset motor neuron disease. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. The major pathological hallmark of ALS is abnormal accumulation of protein inclusions containing TDP-43, FUS or SOD1 protein. Moreover, the focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of a seeded self-propagation with pathogenic prion proteins. In vitro and cell line experimental evidence suggests that SOD1, TDP-43 and FUS form insoluble fibrillar aggregates. Notably, these protein fibrillar aggregates can act as seeds to trigger the aggregation of native counterparts. Collectively, a self-propagation mechanism similar to prion replication and spreading may underlie the pathology of ALS. In this review, we will briefly summarize recent evidence to support the prion-like properties of major ALS-associated proteins and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.

Keywords: ALS (Amyotrophic lateral sclerosis), SOD1, TDP-43, FUS, Plion-like phenomena, Misfolded protein aggregates

The motor neuron diseases (MND) are a class of progressive neurologic diseases characterized by selective degeneration of the motor neurons that govern voluntary muscle movement [1]. Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is the most common form of motor neuron disease. It is a fatal adult-onset (the average disease onset age is approximately 50 years) neurodegenerative disease, and major characteristic symptoms of ALS include muscle weakness, spasticity, atrophy, paralysis and premature death [2]. Motor neurons in the cortex, brain stem and spinal cord gradually degenerate in ALS patients, and most ALS patients die within 3~5 years of disease onset due to respiratory failure. However, approximately 10% of patients survive more than ten years [3]. The incidence rate of ALS is 2 out of 100,000 individuals per year, and the average age of onset is approximately 50 years [2]. ALS is sporadic in 95% of patients and seems to occur randomly throughout the population (called Sporadic ALS (SALS)). The remaining 5% of ALS patients have at least one affected first degree relative (familial ALS (FALS)) [4]. There is no cure for ALS, and riluzole, the only FDA-approved drug for ALS treatment, extends survival by only a few months [5]. Thus, the search for novel therapeutic approaches is warranted.

The first identified ALS disease gene was SOD1 (copper zinc superoxide dismutase 1), which was found in 1993 [6]. Thanks to recent advances in sequencing and genotyping technology, many new genetic mutations have been identified in FALS and SALS patients. These mutations are found in the HNRNPA1, PFN1, TAF15, ATXN2, C9ORF72, UBQLN2, OPTN, VCP, FUS and TARDBP genes [4,7]. Interestingly, the most prominent histopathological hallmark of ALS is the accumulation of misfolded oligomers or protein inclusions containing TDP-43, FUS or SOD1 protein [2]. Moreover, most ALS patients have dense TDP-43 aggregates in affected neurons and glia in the CNS [8].

Despite protein aggregation being a prominent pathological hallmark of ALS, many questions still need to be addressed, especially regarding the pathological role and formation mechanism of these protein aggregates [4]. Recently, it was proposed that cell to cell transmission of misfolded protein aggregates (a prion-like mechanism) may directly contribute to the generation of novel protein aggregates and the propagation of neurodegeneration in ALS and other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease [9,10,11,12,13].

In this review, we highlight the recent findings implicating a prion-like mechanism as a key player in neurodegeneration in ALS patients and discuss the possible therapeutic strategies for ALS based on a prion-like mechanism.

Transmissible spongiform encephalopathies (TSEs), also called prion diseases, are fatal neurodegenerative diseases of mammals. The infectious agent of TSEs is a misfolded protein, referred to as PRPsc [14]. PRPsc aggregates can self-propagate and elongate by binding to monomers of PrPc (normal prion protein) [15]. There are a number of similarities between TSEs and ALS. First of all, ALS patients have an aggregate structure that contains a misfolded self-protein in their affected neurons. Furthermore, recent cultured cell line and animal model studies suggest that the misfolded forms of SOD1 and TDP-43 do self-propagate within neuronal cells and transmit to neighboring cells [9,12,16]. One of the most well-known clinical observations of ALS is focal onset of motor weakness in the spinal and bulbar regions and contagious spreading of the disease [17]. Interestingly, intensive autopsy studies of postmortem ALS patients show that the loss of lower motor neurons is most apparent at the region of onset and decreases in a graded manner with further distance from the anatomic location of disease onset [18]. These clinical data indicate that neurodegeneration in ALS is an orderly propagating process, which seems to share the signature of seeded self-propagation with pathogenic prion proteins.

Despite a number of parallels between prion disease and ALS, the prion-like phenomena observed in ALS are fundamentally different from TSEs. The main characteristic of TSEs is their infectivity. Prion diseases can be transmitted through an animal population via oral uptake, blood transfusion or other sources of direct contact [19]. TDP-43 and SOD1 misfolded protein aggregates found in ALS patients can induce the misfolding of their normally structured counterparts; however, at least under natural circumstances, ALS is not an infectious disease. Therefore, we should differentiate the terms "prion" and "prion-like". The term "prion-like mechanism" will be used to identify the molecular mechanisms that share common features with the self-propagation and spreading characteristics of prion proteins. A summary of the evidence implicating the prion-like mechanism within ALS is shown in Table 1.

SOD1 is a highly conserved, ubiquitously expressed enzyme that scavenges superoxide radicals [13]. Dominant mutations in the gene encoding SOD1 account for approximately 20% of FALS cases [20]. Native SOD1 forms a very stable homodimer, but almost all ALS-linked SOD1 mutations are susceptible to partial unfolding at physiological pH and temperature [21]. Furthermore, mutant SOD1-containing insoluble inclusions are highly accumulated within affected motor neurons of SOD1-related FALS patients [22,23]. Transgenic mice expressing human SOD1 with a pathogenic mutation very accurately recapitulate common characteristics of ALS such as the selective progressive loss of motor neurons and a progressive loss of motor activity [24]. SOD1-positive inclusions found in human patients and FALS mouse-models show identified granule-coated fibrillar morphologies [25]. Fibrillar protein aggregates that are rich in β-sheet structures act as a structural template to convert normal proteins into a misfolded structure and then elongate the protein fibril. It is not clear if SOD1-containing inclusions of FALS patients are β-sheet rich fibrils, but fibrillar aggregates of the SOD1 mouse model contain amyloid-like aggregates with a β-pleated sheet [26]. Moreover, spinal cord homogenates of transgenic mice expressing the ALS-linked G93A-mutant human SOD1 protein triggered amyloid-like fibril formation of purified wild type and mutant SOD1 protein [27]. Other studies also show that wild type and mutant misfolded SOD1 proteins can induce misfolding of cell-endogenous normal structured wild type SOD1 in a physiological intracellular environment [28]. Glad et al. removed misfolded mutant SOD1 proteins using a mutant form specific antibody (GX-CT) in a HEK cell line expressing the SOD1 G127X mutant, but this removal of misfolded seeds did not prevent aggregation of endogenous SOD1 [28]. This result indicates that the newly generated misfolded SOD1 also act as a template for the self-propagation of misfolded SOD1 aggregates.

As mentioned above, many studies suggest that misfolded SOD1-containing fibrils can act as a structural template for a "prion-like replication" from native-structured protein to insoluble misfolded conformers. Misfolded fibrils can be elongated by this conversion process of the normal protein. Breakage of misfolded fibrils is important for this self-propagation process because sheared pieces of misfolded fibrils can be propagated through the template-assisted misfolding of native protein. This self-propagation process is analogous to the replication of infectious prion aggregates (Fig. 1).

Another key feature of prion-like mechanisms is the cell-to-cell spread of misfolded aggregates. Intracellular proteins could be released to the extracellular environment via transport vesicle mediated exocytosis. Another possible process is cell death induced leakage of misfolded seeds. The death of affected cells releases aggregated protein into the extracellular environment, and then neighboring cells can take up these aggregates by phagocytosis (Fig. 2). Progressive neurodegeneration of affected motor neurons is one of the major characteristics of ALS. Therefore, there is a high possibility that seed spreading by cell death is implicated in cell-to-cell transmission of misfolded aggregates. A recent study reported that purified ALS-linked SOD1 mutant aggregates (SOD1H46R) effectively penetrate into cells and convert the endogenous wild type SOD1 to misfolded aggregates in the Neuro-2a cell line [16]. These aggregates are continuously released by cells and taken up into neighboring cells via macropinocytosis [16]. These findings indicate that ALS-linked SOD1 aggregates have prion-like properties such as self-perpetuation and the transmission of the misfolded pathological proteins to adjacent cells.

Misfolded aggregate spreading mediated by secreted mutant SOD1 may not be limited to neuron to neuron propagation. It is very well accepted that secreted toxic factors produced by glial cells expressing ALS-causing mutant SOD1 induce the loss of motor neurons in the FALS SOD1 mouse model [20]. Using astrocytes derived from neural progenitor cells from the postmortem tissues of ALS patients, Haidet-Phillps et al. demonstrated that astrocytes generated from tissues from ALS patients are toxic to motor neurons derived from non-ALS postmortem tissues [29]. Importantly, knock-down of SOD1 in ALS tissue-derived astrocytes was found to mitigate the motor neuron toxicity of these astrocytes [29]. These findings indicate that the generation of a glial cell released factor that is toxic to motor neurons is dependent on the glial SOD1 protein. Furthermore, overexpression of ALS-linked mutant SOD1 in astrocytes induced an increase in exosome release, and those astrocyte-produced exosomes contained mutant SOD1 proteins. Not surprisingly, mutant SOD1 was transmitted to the cytoplasm of spinal neurons through astrocyte-released exosomes [30]. However, additional experimental studies are required to prove that secretory vesicles released from glial cells act as a messenger for misfolded seeding protein.

TAR DNA binding protein (TDP-43, 43 KDa) is a highly conserved RNA/DNA binding protein involved in various RNA processing pathways including stress granule formation and RNA splicing [31]. TDP-43 is a major component of pathological inclusions found in spinal cord motor neurons, hippocampal and frontal cortex neurons and glial cells in most SALS and SOD1-negative FALS cases [4]. Under normal conditions, most TDP-43 protein is localized in the nucleus, however, in ALS patients, neurons with cytoplasmic TDP-43 aggregates often showed a corresponding reduction of the nuclear TDP-43 level [32]. Genetic studies have identified TARDBP (which encodes TDP-43) mutations in ~4% of FALS cases and a small percentage of SALS cases [6]. Following the identification of TARDBP mutations in ALS patients, other FALS mutations were identified in FUS which also encodes the RNA binding protein FUS [33]. Intriguingly, FUS and TDP-43 share a very similar domain structure (Fig. 3), and both purified TDP-43 and FUS can easily aggregate in vitro [4]. Furthermore, both TDP-43 and FUS contain a prion-like glutamine/asparagine rich domain that shares similarities with yeast prion protein, and this domain is essential for amyloid-like fiber polymerization in cell-free models of RNA granule formation [34].

Like SOD1 proteins, the ALS-causing TDP-43 mutation enhances neurotoxicity and abnormal aggregate formation, and the C-terminal domain is essential for this aggregation process [35,36]. Moreover, almost all ALS linked TDP-43 mutations are found in the C-terminal region, and C-terminal truncated fragments of TDP-43 show significantly enhanced aggregation properties in vitro and in cells [20]. Taken together, these data suggest that TDP-43 positive neuronal cytoplasmic inclusions are driven by the prion-like C-terminal domain of TDP-43 and that pathologic aggregation process is accelerated by ALS-linked TDP-43 mutations. A recent study reported that the recombinant TDP-43 protein forms sarkosyl-insoluble fibrillar aggregates in vitro, and transduction of these TDP-43 fibrils into cultured HEK293T cells overexpressing TDP-43 induces fibrillation of the endogenous TDP-43 [11]. Nonaka et al. also demonstrated that the introduction of detergent insoluble TDP-43 aggregates from ALS or FTLD-TDP patients into SH-SY5Y cells expressing TDP-43 induces aggregation of phosphorylated and ubiquitinated TDP-43 in a prion-like, self-templating manner [9]. In addition, phosphorylated TDP-43 aggregates are transmitted between cultured cells, and intracellular TDP-43 aggregates are associated with exosomes [9]. Based upon these results, the prion-like properties of TDP-43 may contribute to the pathological mechanism of ALS.

It remains to be determined whether FUS also shows prion-like propagation, but recent studies have reported that an ALS-causing mutant of FUS forms amyloid-like fibrillar aggregates, and these fibrils act as seeds to trigger the aggregation of wild-type FUS in vitro [37].

Accumulating evidence suggests that the prion-like mechanism of TDP-43 and FUS plays an important role in ALS pathogenesis; however, further studies are needed to elucidate their exact mechanism of action and pathological effect.

The focality of clinical onset and regional spreading of neurodegeneration are typical features of ALS. One of the possible models for the progression of ALS would be the spreading of toxic misfolded seeds from a focal site. If a prion-like mechanism represents key components of disease progression and persistence, antibody-based drug development could be possible. Antibodies could promote break-down of misfolded-aggregates and block their ability to act as a nucleation seed or penetrate into neighboring cells. Interestingly, intracerebroventricular infusion of monoclonal antibodies specific to misfolded SOD1 extends the lifespan of mice with ALS (G93A-SOD1 mouse model) [38].

Another promising therapeutic strategy for ALS involves elucidating the shared pathological mechanism between ALS and Prion diseases. Recent studies indicate that elevation of the eIF2α-phosphorylation level is a common feature of Prion diseases and ALS models [39,40]. Strikingly, downregulation of eIF2α-phosphorylation by PERK inhibitor treatment mitigates the toxicity of Prion proteins and TDP-43 [39, 41].

Consequently, dissecting the molecular mechanism of a prion-like process may yield valuable insights into developing therapeutic strategies for ALS. Therefore, lessons and tools from the prion field may become useful for future research on ALS.

Fig. 1. Proposed model of self-propagation of misfolded protein fibrils in ALS. Misfolded protein aggregates bind to their native counterparts at their end and induce the misfolding of captured protein in a template-directed reaction. This process elongates the misfolded protein fibrils. Amplification of self-templating amyloid-like fibrils is achieved by the fragmentation of amyloid forms to expose new ends. Breakage of misfolded fibrils also allows the dissemination of self-propagating seeds.
Fig. 2. Putative mechanism of trans-cellular spreading of protein aggregates in ALS. Misfolded protein aggregates are released by cell death or exocytosis. Extracellular seeds can penetrate into neighboring cells and this uptake initiates misfolding and aggregation of native counterparts.
Fig. 3. Schematic representation of the domain structure of TDP-43 and FUS. Different protein domains are indicated in different colors. Both proteins contain prion-like and RRM domains. NLS=Nuclear Localization Signal, RRM=RNA Recognition Motif, NES=Nuclear Export signal, Gly-rich=Glycine rich region, SYGQ-rich=Glutamine/Glycine/Serine/Tyrosine rich region, RGG=Arginine/Glycine rich region, ZnF=Zinc finger motif.
Table. 1. Evidence for prion-like mechanisms in ALS

SOD1: Superoxide dismutase1, TDP-43: TAR DNA-binding protein 43, FUS/TLS: Fused in sarcoma/ translocated in liposarcoma, n.d.: not determined..


  1. Vucic S, Rothstein JD, Kiernan MC. Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies. Trends Neurosci 2014;37:433-442.
    Pubmed
  2. Matus S, Valenzuela V, Medinas DB, Hetz C. ER Dysfunction and Protein Folding Stress in ALS. Int J Cell Biol 2013;2013:674751.
    Pubmed
  3. Thomsen GM, Gowing G, Svendsen S, Svendsen CN. The past, present and future of stem cell clinical trials for ALS. Exp Neurol 2014
  4. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol 2013;125:777-794.
    Pubmed
  5. Patten SA, Armstrong GA, Lissouba A, Kabashi E, Parker JA, Drapeau P. Fishing for causes and cures of motor neuron disorders. Dis Model Mech 2014;7:799-809.
    Pubmed
  6. Renton AE, Chió A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 2014;17:17-23.
    Pubmed
  7. Janssens J, Van Broeckhoven C. Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders. Hum Mol Genet 2013;22:R77-R87.
    Pubmed
  8. Lee EB, Lee VM, Trojanowski JQ. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 2012;13:38-50.
    Pubmed
  9. Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H, Hasegawa M. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 2013;4:124-134.
    Pubmed
  10. Münch C, Bertolotti A. Self-propagation and transmission of misfolded mutant SOD1: prion or prion-like phenomenon?. Cell Cycle 2011;10:1711.
    Pubmed
  11. Furukawa Y, Kaneko K, Watanabe S, Yamanaka K, Nukina N. A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J Biol Chem 2011;286:18664-18672.
    Pubmed
  12. Sábado J, Casanovas A, Tarabal O, Hereu M, Piedrafita L, Calderó J, Esquerda JE. Accumulation of misfolded SOD1 in dorsal root ganglion degenerating proprioceptive sensory neurons of transgenic mice with amyotrophic lateral sclerosis. Biomed Res Int 2014;2014:852163.
    Pubmed
  13. Marciniuk K, Taschuk R, Napper S. Evidence for prion-like mechanisms in several neurodegenerative diseases: potential implications for immunotherapy. Clin Dev Immunol 2013;2013:473706.
    Pubmed
  14. Corsaro A, Thellung S, Villa V, Nizzari M, Florio T. Role of prion protein aggregation in neurotoxicity. Int J Mol Sci 2012;13:8648-8669.
    Pubmed
  15. Kabir ME, Safar JG. Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases. Prion 2014;8:111-116.
    Pubmed
  16. Münch C, O'Brien J, Bertolotti A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci U S A 2011;108:3548-3553.
    Pubmed
  17. Verma A. Protein aggregates and regional disease spread in ALS is reminiscent of prion-like pathogenesis. Neurol India 2013;61:107-110.
    Pubmed
  18. Ravits J, Laurie P, Fan Y, Moore DH. Implications of ALS focality: rostral-caudal distribution of lower motor neuron loss postmortem. Neurology 2007;68:1576-1582.
    Pubmed
  19. Gough KC, Maddison BC. Prion transmission: prion excretion and occurrence in the environment. Prion 2010;4:275-282.
    Pubmed
  20. Polymenidou M, Cleveland DW. The seeds of neurodegeneration: prion-like spreading in ALS. Cell 2011;147:498-508.
    Pubmed
  21. Tiwari A, Hayward LJ. Mutant SOD1 instability: implications for toxicity in amyotrophic lateral sclerosis. Neurodegener Dis 2005;2:115-127.
    Pubmed
  22. Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, Reaume AG, Scott RW, Cleveland DW. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 1998;281:1851-1854.
    Pubmed
  23. Rotunno MS, Bosco DA. An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis. Front Cell Neurosci 2013;7:253.
    Pubmed
  24. Heiman-Patterson TD, Sher RB, Blankenhorn EA, Alexander G, Deitch JS, Kunst CB, Maragakis N, Cox G. Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: a window of opportunity in the search for genetic modifiers. Amyotroph Lateral Scler 2011;12:79-86.
    Pubmed
  25. Kato S, Takikawa M, Nakashima K, Hirano A, Cleveland DW, Kusaka H, Shibata N, Kato M, Nakano I, Ohama E. New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (SOD1) gene mutations: inclusions containing SOD1 in neurons and astrocytes. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:163-184.
    Pubmed
  26. Furukawa Y, Kaneko K, Yamanaka K, O'Halloran TV, Nukina N. Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis. J Biol Chem 2008;283:24167-24176.
    Pubmed
  27. Chia R, Tattum MH, Jones S, Collinge J, Fisher EM, Jackson GS. Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis. PLoS One 2010;5:e10627.
    Pubmed
  28. Grad LI, Guest WC, Yanai A, Pokrishevsky E, O'Neill MA, Gibbs E, Semenchenko V, Yousefi M, Wishart DS, Plotkin SS, Cashman NR. Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc Natl Acad Sci U S A 2011;108:16398-16403.
    Pubmed
  29. Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, Rao M, Eagle A, Kammesheidt A, Christensen A, Mendell JR, Burghes AH, Kaspar BK. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 2011;29:824-828.
    Pubmed
  30. Basso M, Pozzi S, Tortarolo M, Fiordaliso F, Bisighini C, Pasetto L, Spaltro G, Lidonnici D, Gensano F, Battaglia E, Bendotti C, Bonetto V. Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis. J Biol Chem 2013;288:15699-15711.
    Pubmed
  31. Baloh RH. TDP-43: the relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. FEBS J 2011;278:3539-3549.
    Pubmed
  32. Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H, Eisen A, McClusky L, Kretzschmar HA, Monoranu CM, Highley JR, Kirby J, Siddique T, Shaw PJ, Lee VM, Trojanowski JQ. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 2007;61:427-434.
    Pubmed
  33. Gitler AD, Shorter J. RNA-binding proteins with prion-like domains in ALS and FTLD-U. Prion 2011;5:179-187.
    Pubmed
  34. Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, Mirzaei H, Goldsmith EJ, Longgood J, Pei J, Grishin NV, Frantz DE, Schneider JW, Chen S, Li L, Sawaya MR, Eisenberg D, Tycko R, McKnight SL. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 2012;149:753-767.
    Pubmed
  35. Guo W, Chen Y, Zhou X, Kar A, Ray P, Chen X, Rao EJ, Yang M, Ye H, Zhu L, Liu J, Xu M, Yang Y, Wang C, Zhang D, Bigio EH, Mesulam M, Shen Y, Xu Q, Fushimi K, Wu JY. An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol 2011;18:822-830.
    Pubmed
  36. Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem 2009;284:20329-20339.
    Pubmed
  37. Nomura T, Watanabe S, Kaneko K, Yamanaka K, Nukina N, Furukawa Y. Intranuclear aggregation of mutant FUS/TLS as a molecular pathomechanism of amyotrophic lateral sclerosis. J Biol Chem 2014;289:1192-1202.
    Pubmed
  38. Gros-Louis F, Soucy G, Larivière R, Julien JP. Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS. J Neurochem 2010;113:1188-1199.
    Pubmed
  39. Kim HJ, Raphael AR, LaDow ES, McGurk L, Weber RA, et al. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet 2014;46:152-160.
    Pubmed
  40. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 2012;485:507-511.
    Pubmed
  41. Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, Mallucci GR. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013;5:206ra138.
  42. Vande Velde C, Miller TM, Cashman NR, Cleveland DW. Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci U S A 2008;105:4022-4027.
    Pubmed
  43. Zetterström P, Andersen PM, Brännström T, Marklund SL. Misfolded superoxide dismutase-1 in CSF from amyotrophic lateral sclerosis patients. J Neurochem 2011;117:91-99.
    Pubmed