Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 145 No. 0506 (2015)

Advances and challenges in understanding the multifaceted pathogenesis of amyotrophic lateral sclerosis

  • Florent Laferriere
  • Magdalini Polymenidou
DOI
https://doi.org/10.4414/smw.2015.14054
Cite this as:
Swiss Med Wkly. 2015;145:w14054
Published
25.01.2015

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, which primarily affects motor neurons leading to progressive paralysis and death within a few years from onset. The pathological hallmark of ALS is the presence of cytoplasmic ubiquitinated protein inclusions in motor neurons and glial cells primarily in the spinal cord. While the vast majority of ALS occurs sporadically (sALS), in ~10% of cases, called familial ALS (fALS), there is clear indication of genetic inheritance. In the last decade, enormous progress was made in unravelling the aetiology of the disease, with the identification of ALS-causing mutations in new genes, as well as key molecular players involved in the origin or progression of ALS. However, much more needs to be done, as the pathogenic mechanisms triggered by a genetic or sporadic event leading to cytotoxicity and neuronal cell death are still poorly understood. The recent discoveries offer new possibilities for devising experimental animal and cellular models, which will hopefully contribute to the development of new techniques for early diagnosis and the identification of therapeutic targets for ALS. Here we review the current understanding of the aetiology, genetics, and pathogenic factors and mechanisms of ALS. We also discuss the challenges in deciphering ALS pathogenesis that result from the high complexity and heterogeneity of the disease.

References

  1. Lacomblez L, et al. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996;347(9013):1425–31.
  2. Diagnosis ETFo, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) – revised report of an EFNS task force. Eur J Neurol. 2012;19(3):360–75.
  3. Caselli RJ, et al. Rapidly progressive aphasic dementia and motor neuron disease. Ann Neurol. 1993;33(2):200–7.
  4. Neary D, Snowden JS, Mann DM. Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS). J Neurol Sci. 2000;180(1–2):15–20.
  5. Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 2002;59(7):1077–9.
  6. Ringholz GM, et al. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005;65(4):586–90.
  7. Mackenzie IRA, Rademakers R. The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments. Neurogenetics. 2007;8(4):237–48.
  8. Polymenidou M, et al. Misregulated RNA processing in amyotrophic lateral sclerosis. Brain Res. 2012;1462:3–15.
  9. Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013;79(3):416–38.
  10. Rosen DR, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59–62.
  11. Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006;7(9):710–23.
  12. Ilieva H, Polymenidou M, Cleveland DW. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol. 2009;187(6):761–72.
  13. Gitcho MA, et al. TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol. 2008;63(4):535–8.
  14. Kabashi E, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008;40(5):572–4.
  15. Yokoseki A, et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008;63(4):538–42.
  16. Sreedharan J, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319(5870):1668–72.
  17. Van Deerlin VM, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7(5):409–16.
  18. Vance C, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208–11.
  19. Kwiatkowski TJ, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205–8.
  20. DeJesus-Hernandez M, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245–56.
  21. Renton AE, et al. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21–Linked ALS-FTD. Neuron. 2011: p. 1–19.
  22. Rademakers R, van Blitterswijk M. Motor neuron disease in 2012: Novel causal genes and disease modifiers. Nat Rev Neurol. 2013;9(2):63–4.
  23. Renton AE, Chio A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17–23.
  24. Alderman EM, et al. Angiogenic activity of human tumor plasma membrane components. Biochemistry. 1985;24(27):7866–71.
  25. Chio A, et al. A de novo missense mutation of the FUS gene in a “true” sporadic ALS case. Neurobiol Aging. 2011;32(3):553 e23–6.
  26. Dejesus-Hernandez M, et al. De novo truncating FUS gene mutation as a cause of sporadic amyotrophic lateral sclerosis. Hum Mutat. 2010;31(5):E1377–E1389.
  27. Lattante S, et al. Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease. Neurology. 2012.
  28. Pamphlett R, et al. Transmission of C9orf72 hexanucleotide repeat expansions in sporadic amyotrophic lateral sclerosis: an Australian trio study. Neuroreport, 2012.
  29. van der Zee J, et al. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat. 2013;34(2):363–73.
  30. Cruts M, et al. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci. 2013;36(8):450–9.
  31. Neumann M, et al. Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Science. 2006;314(5796):130–3.
  32. Arai T, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351(3):602–11.
  33. Tan C-F, et al. TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol. 2007;113(5):535–42.
  34. Mackenzie IRA, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007;61(5):427–34.
  35. Kerman A, et al. Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form. Acta Neuropathol. 2010;119(3):335–44.
  36. Al-Sarraj S, et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72–linked FTLD and MND/ALS. Acta Neuropathol. 2011;122(6):691–702.
  37. Troakes C, et al. An MND/ALS phenotype associated with C9orf72 repeat expansion: abundant p62–positive, TDP-43–negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology. 2012;32(5):505–14.
  38. Ash PEA, et al. Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS. Neuron. 2013;77(4):639–46.
  39. Mori K, et al. The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS. Science, 2013.
  40. Zu T, et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A. 2013;110(51):E4968–77.
  41. Lagier-Tourenne C, et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013;110(47):E4530–9.
  42. Bruijn LI, et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1–containing inclusions. Neuron. 1997;18(2):327–38.
  43. Rakhit R, et al. Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis. J Biol Chem. 2002;277(49):47551–6.
  44. Furukawa Y, et al. Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis. J Biol Chem. 2008;283(35):24167–76.
  45. Basso M, et al. Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. J Biol Chem. 2006;281(44):33325–35.
  46. Brotherton TE, et al. Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS. Proc. Natl Acad Sci U S A. 2012;109(14):5505–10.
  47. Bosco DA, et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci. 2010;13(11):1396–403.
  48. Lagier-Tourenne C, Polymenidou M, Cleveland DW. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Human Molecular Genetics. 2010;19(R1):R46–R64.
  49. Alami NH, et al. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron. 2014;81(3):536–43.
  50. Wang I-F, et al. TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J Neurochem. 2008;105(3):797–806.
  51. Colombrita C, et al. TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem. 2009;111(4):1051–61.
  52. Dewey CM, et al. TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol Cell Biol. 2011;31(5):1098–108.
  53. Anderson P, Kedersha N. RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat Rev Mol Cell Biol. 2009;10(6):430–6.
  54. Igaz LM, et al. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol. 2008;173(1):182–94.
  55. Sun Z, et al. Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol. 2011;9(4):e1000614.
  56. Polymenidou M, Cleveland DW. The seeds of neurodegeneration: prion-like spreading in ALS. Cell. 2011;147(3):498–508.
  57. Dormann D, et al. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. The EMBO Journal. 2010;29(16):2841–57.
  58. Bentmann E, et al. Requirements for stress granule recruitment of fused in Sarcoma (FUS) and TAR DNA binding protein of 43 kDa (TDP-43). J Biol Chem. 2012.
  59. Dormann D, et al. Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. The EMBO Journal. 2012: p. 1–18.
  60. Mackenzie IRA, et al. Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neuropathol. 2011;122(1):87–98.
  61. Gijselinck I, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2012;11(1):54–65.
  62. Majounie E, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11(4):323–30.
  63. Zhang D, et al. Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease. Front Genet. 2012;3:283.
  64. Levine TP, et al. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics. 2013;29(4):499–503.
  65. Farg MA, et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet. 2014.
  66. Geser F, et al. Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol. 2008;65(5):636–41.
  67. Geser F, et al. Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch. Neurol. 2009;66(2):180–9.
  68. May S, et al. C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol. 2014.
  69. Mori K, et al. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62–positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol. 2013;125(3):413–23.
  70. Mizielinska S, et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014.
  71. Reaume AG, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet. 1996;13(1):43–7.
  72. Gurney ME, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 1994;264(5166):1772–5.
  73. Bruijn LI, et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science. 1998;281(5384):1851–4.
  74. Epstein CJ, et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc Natl Acad Sci U S A. 1987;84(22):8044–8.
  75. Schickler M, et al. Diminished serotonin uptake in platelets of transgenic mice with increased Cu/Zn-superoxide dismutase activity. EMBO J. 1989;8(5):1385–92.
  76. Graffmo KS, et al. Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis. Hum Mol Genet. 2013;22(1):51–60.
  77. Wu L-S, et al. TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis. 2010;48(1):56–62.
  78. Sephton CF, et al. TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem. 2010;285(9):6826–34.
  79. Kraemer BC, et al. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol. 2010;119(4):409–19.
  80. Wu LS, Cheng WC, Shen CK. Targeted Depletion of TDP-43 Expression in the Spinal Cord Motor Neurons Leads to the Development of Amyotrophic Lateral Sclerosis (ALS)-like Phenotypes in Mice. Journal of Biological Chemistry. 2012.
  81. Iguchi Y, et al. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain. 2013.
  82. Yang C, et al. Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2014;111(12):E1121–9.
  83. Wegorzewska I, et al. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2009;106(44):18809–14.
  84. Zhou H, et al. Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet. 2010;6(3):e1000887.
  85. Igaz LM, et al. Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest. 2011;121(2):726–38.
  86. Huang C, et al. Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats. J Clin Invest. 2012;122(1):107–18.
  87. Arnold ES, et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A. 2013;110(8):E736–45.
  88. Wils H, et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2010;107(8):3858–63.
  89. Hicks GG, et al. Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat Genet. 2000;24(2):175–9.
  90. Kuroda M, et al. Male sterility and enhanced radiation sensitivity in TLS(-/-) mice. The EMBO Journal. 2000;19(3):453–62.
  91. Huang C, et al. FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet. 2011;7(3):e1002011.
  92. Mitchell JC, et al. Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol. 2012.
  93. Suzuki N, et al. The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD. Nat Neurosci. 2013;16(12):1725–7.
  94. Panda SK, et al. Highly efficient targeted mutagenesis in mice using TALENs. Genetics. 2013;195(3):703–13.
  95. Donnelly CJ, et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron. 2013;80(2):415–28.
  96. Sareen D, et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med. 2013;5(208):208ra149.
  97. Almeida S, et al. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 2013;126(3):385–99.
  98. Wainger BJ, et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014;7(1):1–11.
  99. Jaarsma D, et al. Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J Neurosci. 2008;28(9):2075–88.
  100. Ralph GS, et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med. 2005;11(4):429–33.
  101. Boillee S, et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006;312(5778):1389–92.
  102. Yamanaka K, et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci. 2008;11(3):251–3.
  103. Kang SH, et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci. 2013;16(5):571–9.
  104. Rothstein JD, et al. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 1995;38(1):73–84.
  105. Howland DS, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A. 2002;99(3):1604–9.
  106. Morel L, et al. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem. 2013;288(10):7105–16.
  107. van Zundert B, et al. Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J Neurosci. 2008;28(43):10864–74.
  108. Saxena S, Caroni P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron. 2011;71(1):35–48.
  109. Kikuchi H, et al. Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc Natl Acad Sci U S A. 2006;103(15):6025–30.
  110. Nishitoh H, et al. ALS-linked mutant SOD1 induces ER stress- and ASK1–dependent motor neuron death by targeting Derlin-1. Genes Dev. 2008;22(11):1451–64.
  111. Saxena S, Cabuy E, Caroni P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nature Publishing Group. 2009;12(5):627–36.
  112. Kiskinis E, et al. Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1. Cell Stem Cell. 2014.
  113. Bendotti C, et al. Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response. Progr Neurobiol. 2012;97(2):101–26.
  114. Chen S, et al. Autophagy Dysregulation in Amyotrophic Lateral Sclerosis. Brain Pathology. 2011;22(1):110–6.
  115. Liu J, et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron. 2004;43(1):5–17.
  116. Vande Velde C, et al. Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci U S A. 2008;105(10):4022–7.
  117. Zhao W, et al. Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia. 2010;58(2):231–43.
  118. Harraz MM, et al. SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest. 2008;118(2):659–70.
  119. Williamson TL, Cleveland DW. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci. 1999;2(1):50–6.
  120. Zhong Z, et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci. 2008;11(4):420–2.
  121. Polymenidou M, et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci. 2011;14(4):459–68.
  122. Tollervey JR, et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci. 2011;14(4):452–8.
  123. Lagier-Tourenne C, et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci. 2012;15(11):1488–97.
  124. Rogelj B, et al. Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci Rep. 2012;2:603.
  125. Johnson BS, et al. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem. 2009;284(30):20329–39.
  126. Elden AC, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466(7310):1069–75.
  127. Voigt A, et al. TDP-43-mediated neuron loss in vivo requires RNA-binding activity. PLoS ONE. 2010;5(8):e12247.
  128. Kim HJ, et al. Therapeutic modulation of eIF2alpha phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet. 2014;46(2):152–60.
  129. Xi Z, et al. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet. 2013;92(6):981–9.
  130. Haeusler AR, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014;507(7491):195–200.
  131. Zhang YJ, et al. Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol. 2014.
  132. Su Z, et al. Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS. Neuron. 2014.
  133. Kwon I, et al. Poly-dipeptides encoded by the C9ORF72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science. 2014.
  134. Aguzzi A, Polymenidou M. Mammalian prion biology: one century of evolving concepts. Cell. 2004;116(2):313–27.
  135. Aguzzi A. Cell biology: Beyond the prion principle., in Nature. 2009; p. 924–5.
  136. Meyer-Luehmann M, et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006;313(5794):1781–4.
  137. Clavaguera F, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11(7):909–13.
  138. Luk KC, et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338(6109):949–53.
  139. Prudencio M, et al. Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. Human Molecular Genetics. 2009;18(17):3217–26.
  140. Chia R, et al. Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis. PLoS ONE. 2010;5(5):e10627.
  141. Hayward LJ, et al. Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis. J Biol Chem. 2002;277(18):15923–31.
  142. Münch C, J. O'Brien, Bertolotti A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci U S A. 2011;108(9):3548–53.
  143. Furukawa Y, Torres AS, O’Halloran TV. Oxygen-induced maturation of SOD1: a key role for disulfide formation by the copper chaperone CCS. EMBO J. 2004;23(14):2872–81.
  144. Grad LI, et al. Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc Natl Acad Sci U S A. 2011;108(39):16398–403.
  145. Furukawa Y, et al. Intracellular seeded aggregation of mutant Cu,Zn-superoxide dismutase associated with amyotrophic lateral sclerosis. FEBS Lett. 2013;587(16):2500–5.
  146. Furukawa Y, et al. A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J Biol. Chem. 2011;286(21):18664–72.
  147. Guo W, et al. An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol. 2011;18(7):822–30.
  148. Nonaka T, et al. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 2013;4(1):124–34.
  149. Ayala YM, et al. TDP-43 regulates its mRNA levels through a negative feedback loop. The EMBO Journal. 2011;30(2):277–88.
  150. Zhou Y, et al. ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLoS Genet. 2013;9(10):e1003895.

Most read articles by the same author(s)