Skip to main content
SpringerLink
Log in

Motoneuron Disease: Basic Science

  • Chapter
  • First Online:
Neurodegenerative Diseases

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 15))

Abstract

ALS is a relentless neurodegenerative disease in which motor neurons are the susceptible neuronal population. Their death results in progressive paresis of voluntary and respiratory muscles. The unprecedented rate of discoveries over the last two decades have broadened our knowledge of genetic causes and helped delineate molecular pathways. Here we critically review ALS epidemiology, genetics, pathogenic mechanisms, available animal models, and iPS cell technologies with a focus on their translational therapeutic potential. Despite limited clinical success in treatments to date, the new discoveries detailed here offer new models for uncovering disease mechanisms as well as novel strategies for intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ALS:

Amyotrophic lateral sclerosis

ATXN2:

Ataxin 2

C9ORF72:

Chromosome 9 open reading frame 72

FTD:

Fronto-temporal dementia (FTD)

FUS/TLS:

Fused in sarcoma/translocated in liposarcoma

HRE:

Hexanucleotide repeat expansion

SOD1:

Superoxide dismutase 1

TDP-43:

43 kDa, transactive response DNA/RNA-binding protein

References

  1. Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2(11):806–819

    Article  CAS  PubMed  Google Scholar 

  2. Seltman RE, Matthews BR (2012) Frontotemporal lobar degeneration: epidemiology, pathology, diagnosis and management. CNS Drugs 26(10):841–870

    Article  CAS  PubMed  Google Scholar 

  3. Lillo P et al (2012) Amyotrophic lateral sclerosis and frontotemporal dementia: a behavioural and cognitive continuum. Amyotroph Lateral Scler 13(1):102–109

    Article  PubMed  Google Scholar 

  4. Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59(7):1077–1079

    Article  PubMed  Google Scholar 

  5. Logroscino G et al (2010) Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry 81(4):385–390

    Article  PubMed  Google Scholar 

  6. McGuire V et al (1996) Incidence of amyotrophic lateral sclerosis in three counties in western Washington state. Neurology 47(2):571–573

    Article  CAS  PubMed  Google Scholar 

  7. Harper CJ, Sorenson EJ, Mandrekar J (2015) Epidemiology of amyotrophic lateral sclerosis in Minnesota: a year-long population based study. Amyotroph Lateral Scler Frontotemporal Degener (1–4)

    Google Scholar 

  8. Beghi E et al (2007) Incidence of ALS in Lombardy, Italy. Neurology 68(2):141–145

    Article  CAS  PubMed  Google Scholar 

  9. Vazquez MC et al (2008) Incidence and prevalence of amyotrophic lateral sclerosis in Uruguay: a population-based study. Neuroepidemiology 30(2):105–111

    Article  CAS  PubMed  Google Scholar 

  10. Okumura H et al (1992) Epidemiological study of motor neuron disease in Hokkaido island--its incidence, prevalence and regional distributions--ALS Study Group. No To Shinkei 44(8):727–732

    CAS  PubMed  Google Scholar 

  11. Johnston CA et al (2006) Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol 253(12):1642–1643

    Article  PubMed  Google Scholar 

  12. Ingre C et al (2015) Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol 7:181–193

    PubMed  PubMed Central  Google Scholar 

  13. Lannuzel A et al (2015) Clinical varieties and epidemiological aspects of amyotrophic lateral sclerosis in the Caribbean island of Guadeloupe: a new focus of ALS associated with parkinsonism. Amyotroph Lateral Scler Frontotemporal Degener 16(3–4):216–223

    Article  CAS  PubMed  Google Scholar 

  14. Scarmeas N et al (2002) Premorbid weight, body mass, and varsity athletics in ALS. Neurology 59(5):773–775

    Article  CAS  PubMed  Google Scholar 

  15. Beard JD, Kamel F (2015) Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology and survival. Epidemiol Rev 37:55–70

    Article  PubMed  Google Scholar 

  16. Hamidou B et al (2014) Epidemiological evidence that physical activity is not a risk factor for ALS. Eur J Epidemiol 29(7):459–475

    Article  PubMed  Google Scholar 

  17. Huisman MH et al (2013) Lifetime physical activity and the risk of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 84(9):976–981

    Article  PubMed  Google Scholar 

  18. Pupillo E et al (2014) Physical activity and amyotrophic lateral sclerosis: a European population-based case-control study. Ann Neurol 75(5):708–716

    Article  PubMed  Google Scholar 

  19. Pupillo E et al (2012) Trauma and amyotrophic lateral sclerosis: a case-control study from a population-based registry. Eur J Neurol 19(12):1509–1517

    Article  CAS  PubMed  Google Scholar 

  20. Peters TL et al (2013) Severe head injury and amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 14(4):267–272

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ascherio A et al (2005) Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann Neurol 57(1):104–110

    Article  CAS  PubMed  Google Scholar 

  22. Wang H et al (2011) Vitamin E intake and risk of amyotrophic lateral sclerosis: a pooled analysis of data from 5 prospective cohort studies. Am J Epidemiol 173(6):595–602

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fitzgerald KC et al (2014) Dietary omega-3 polyunsaturated fatty acid intake and risk for amyotrophic lateral sclerosis. JAMA Neurol 71(9):1102–1110

    Article  PubMed  PubMed Central  Google Scholar 

  24. Veldink JH et al (2007) Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 78(4):367–371

    Article  CAS  PubMed  Google Scholar 

  25. Graf M et al (2005) High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. J Neural Transm 112(5):649–660

    Article  CAS  PubMed  Google Scholar 

  26. Desnuelle C et al (2001) A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol study group. Amyotroph Lateral Scler Other Motor Neuron Disord 2(1):9–18

    Article  CAS  PubMed  Google Scholar 

  27. Fang F et al (2010) Association between blood lead and the risk of amyotrophic lateral sclerosis. Am J Epidemiol 171(10):1126–1133

    Article  PubMed  PubMed Central  Google Scholar 

  28. Roos PM et al (2012) Manganese in cerebrospinal fluid and blood plasma of patients with amyotrophic lateral sclerosis. Exp Biol Med (Maywood) 237(7):803–810

    Article  CAS  Google Scholar 

  29. Meyer-Baron M et al (2013) The neurobehavioral impact of manganese: results and challenges obtained by a meta-analysis of individual participant data. Neurotoxicology 36:1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kamel F et al (2012) Pesticide exposure and amyotrophic lateral sclerosis. Neurotoxicology 33(3):457–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Malek AM et al (2012) Pesticide exposure as a risk factor for amyotrophic lateral sclerosis: a meta-analysis of epidemiological studies: pesticide exposure as a risk factor for ALS. Environ Res 117:112–119

    Article  CAS  PubMed  Google Scholar 

  32. Cox PA, Sacks OW (2002) Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam. Neurology 58(6):956–959

    Article  PubMed  Google Scholar 

  33. Bradley WG et al (2013) Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases? Amyotroph Lateral Scler Frontotemporal Degener 14(5–6):325–333

    Article  CAS  PubMed  Google Scholar 

  34. Paez-Colasante X et al (2015) Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era. Nat Rev Neurol 11(5):266–279

    Article  CAS  PubMed  Google Scholar 

  35. Al-Chalabi A et al (2010) An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry 81(12):1324–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Peters OM, Ghasemi M, Brown RH Jr (2015) Emerging mechanisms of molecular pathology in ALS. J Clin Invest 125(6):2548

    Article  PubMed  PubMed Central  Google Scholar 

  37. Marangi G, Traynor BJ (2015) Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges. Brain Res 1607:75–93

    Article  CAS  PubMed  Google Scholar 

  38. Neumann M et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133

    Article  CAS  PubMed  Google Scholar 

  39. Kwiatkowski TJ Jr et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323(5918):1205–1208

    Article  CAS  PubMed  Google Scholar 

  40. Vance C et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323(5918):1208–1211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lagier-Tourenne C, Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136(6):1001–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim HJ et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495(7442):467–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nousiainen HO et al (2008) Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet 40(2):155–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Johnson JO et al (2014) Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci 17(5):664–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. DeJesus-Hernandez M et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2):245–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Renton AE et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2):257–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gijselinck I et al (2012) 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 11(1):54–65

    Article  CAS  PubMed  Google Scholar 

  48. Levine TP et al (2013) The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 29(4):499–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Farg MA et al (2014) C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 23(13):3579–3595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Todd PK, Paulson HL (2010) RNA-mediated neurodegeneration in repeat expansion disorders. Ann Neurol 67(3):291–300

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79(3):416–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. van Blitterswijk M, DeJesus-Hernandez M, Rademakers R (2012) How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders? Curr Opin Neurol 25(6):689–700

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Xi Z et al (2014) Hypermethylation of the CpG-island near the C9orf72 G(4)C(2)-repeat expansion in FTLD patients. Hum Mol Genet 23(21):5630–5637

    Article  CAS  PubMed  Google Scholar 

  54. Xi Z et al (2015) The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients. Acta Neuropathol 129(5):715–727

    Article  CAS  PubMed  Google Scholar 

  55. Xi Z et al (2013) Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet 92(6):981–989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mori K et al (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339(6125):1335–1338

    Article  CAS  PubMed  Google Scholar 

  57. Ash PE et al (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77(4):639–646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Majounie E et al (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11(4):323–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Smith BN et al (2013) The C9ORF72 expansion mutation is a common cause of ALS+/− FTD in Europe and has a single founder. Eur J Hum Genet 21(1):102–108

    Article  CAS  PubMed  Google Scholar 

  60. Deng HX et al (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477(7363):211–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Smith BN et al (2014) Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84(2):324–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gros-Louis F et al (2004) A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. J Biol Chem 279(44):45951–45956

    Article  CAS  PubMed  Google Scholar 

  63. Wu CH et al (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488(7412):499–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Taylor JP (2015) Multisystem proteinopathy: intersecting genetics in muscle, bone, and brain degeneration. Neurology 85(8):658–660

    Article  PubMed  Google Scholar 

  65. Landers JE et al (2009) Reduced expression of the kinesin-associated protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 106(22):9004–9009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. van Doormaal PT et al (2014) Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study. Neurobiol Aging 35(10):2420e13–4

    Google Scholar 

  67. van Es MA et al (2011) Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis. Ann Neurol 70(6):964–973

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Elden AC et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466(7310):1069–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chio A et al (2015) ATXN2 polyQ intermediate repeats are a modifier of ALS survival. Neurology 84(3):251–258

    Article  CAS  PubMed  Google Scholar 

  70. van Blitterswijk M et al (2014) Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. Neurobiol Aging 35(10):2421e13–7

    Google Scholar 

  71. van Blitterswijk M et al (2012) Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet 21(17):3776–3784

    Article  PubMed  CAS  Google Scholar 

  72. Polymenidou M et al (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14(4):459–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tollervey JR et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14(4):452–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gregory RI et al (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432(7014):235–240

    Article  CAS  PubMed  Google Scholar 

  75. Ling SC et al (2010) ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci U S A 107(30):13318–13323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Freibaum BD et al (2010) Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res 9(2):1104–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lagier-Tourenne C et al (2012) Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci 15(11):1488–1497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Rogelj B et al (2012) Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci Rep 2:603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Alami NH et al (2014) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81(3):536–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sephton CF et al (2010) TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem 285(9):6826–6834

    Article  CAS  PubMed  Google Scholar 

  81. Kraemer BC et al (2010) Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol 119(4):409–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wu LS et al (2010) TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 48(1):56–62

    CAS  PubMed  Google Scholar 

  83. Schmid B et al (2013) Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci U S A 110(13):4986–4991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Feiguin F et al (2009) Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett 583(10):1586–1592

    Article  CAS  PubMed  Google Scholar 

  85. Chiang PM et al (2010) Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci U S A 107(37):16320–16324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Iguchi Y et al (2013) Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136(Pt 5):1371–1382

    Article  PubMed  Google Scholar 

  87. Wu LS, Cheng WC, Shen CK (2012) Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J Biol Chem 287(33):27335–27344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dewey CM et al (2012) TDP-43 aggregation in neurodegeneration: are stress granules the key? Brain Res 1462:16–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Li YR et al (2013) Stress granules as crucibles of ALS pathogenesis. J Cell Biol 201(3):361–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dewey CM et al (2011) TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol Cell Biol 31(5):1098–1108

    Article  CAS  PubMed  Google Scholar 

  91. Liu-Yesucevitz, L., et al., Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One, 2010. 5(10): p. e13250.

    Google Scholar 

  92. Andersson MK et al (2008) The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response. BMC Cell Biol 9:37

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Bosco DA et al (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet 19(21):4160–4175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Dormann D et al (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29(16):2841–2857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gal J et al (2011) Nuclear localization sequence of FUS and induction of stress granules by ALS mutants. Neurobiol Aging 32(12):2323e27–40

    Article  CAS  Google Scholar 

  96. Kino Y et al (2011) Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. Nucleic Acids Res 39(7):2781–2798

    Article  CAS  PubMed  Google Scholar 

  97. Yasuda K et al (2013) The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules. J Cell Biol 203(5):737–746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Okamoto K, Mizuno Y, Fujita Y (2008) Bunina bodies in amyotrophic lateral sclerosis. Neuropathology 28(2):109–115

    Article  PubMed  Google Scholar 

  99. Caughey B, Lansbury PT (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26:267–298

    Article  CAS  PubMed  Google Scholar 

  100. Lindberg MJ et al (2005) Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants. Proc Natl Acad Sci U S A 102(28):9754–9759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Chung J et al (2003) Cu/Zn superoxide dismutase can form pore-like structures. Biochem Biophys Res Commun 312(4):873–876

    Article  CAS  PubMed  Google Scholar 

  102. Kim J et al (2014) Dimerization, oligomerization, and aggregation of human amyotrophic lateral sclerosis copper/zinc superoxide dismutase 1 protein mutant forms in live cells. J Biol Chem 289(21):15094–15103

    Article  CAS  PubMed  Google Scholar 

  103. Bosco DA et al (2010) Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci 13(11):1396–1403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Forsberg, K., et al., Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients. PLoS One, 2010. 5(7): p. e11552.

    Google Scholar 

  105. Kerman A et al (2010) Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form. Acta Neuropathol 119(3):335–344

    Article  PubMed  Google Scholar 

  106. Liu HN et al (2009) Lack of evidence of monomer/misfolded superoxide dismutase-1 in sporadic amyotrophic lateral sclerosis. Ann Neurol 66(1):75–80

    Article  CAS  PubMed  Google Scholar 

  107. Israelson A et al (2015) Macrophage migration inhibitory factor as a chaperone inhibiting accumulation of misfolded SOD1. Neuron 86(1):218–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Beckman JS et al (1993) ALS, SOD and peroxynitrite. Nature 364(6438):584

    Article  CAS  PubMed  Google Scholar 

  109. Estevez AG et al (1999) Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science 286(5449):2498–2500

    Article  CAS  PubMed  Google Scholar 

  110. Harraz MM et al (2008) SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest 118(2):659–670

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Tiwari A, Xu Z, Hayward LJ (2005) Aberrantly increased hydrophobicity shared by mutants of cu,Zn-superoxide dismutase in familial amyotrophic lateral sclerosis. J Biol Chem 280(33):29771–29779

    Article  CAS  PubMed  Google Scholar 

  112. Rothstein JD et al (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38(1):73–84

    Article  CAS  PubMed  Google Scholar 

  113. van Zundert B et al (2008) Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J Neurosci 28(43):10864–10874

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Saxena S, Cabuy E, Caroni P (2009) A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci 12(5):627–636

    Article  CAS  PubMed  Google Scholar 

  115. Magrane J et al (2012) Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci 32(1):229–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Vande Velde, C., et al., Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS One, 2011. 6(7): p. e22031.

    Google Scholar 

  117. Israelson A et al (2010) Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron 67(4):575–587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Williamson TL, Cleveland DW (1999) Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci 2(1):50–56

    Article  CAS  PubMed  Google Scholar 

  119. Morfini, G.A., et al., Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase. PLoS One, 2013. 8(6): p. e65235.

    Google Scholar 

  120. Pun S et al (2006) Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9(3):408–419

    Article  CAS  PubMed  Google Scholar 

  121. Arai T et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351(3):602–611

    Article  CAS  PubMed  Google Scholar 

  122. Uryu K et al (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67(6):555–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Schwab C et al (2008) Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J Neuropathol Exp Neurol 67(12):1159–1165

    Article  PubMed  Google Scholar 

  124. Hasegawa M et al (2007) TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain 130(Pt 5):1386–1394

    Article  PubMed  Google Scholar 

  125. Inukai Y et al (2008) Abnormal phosphorylation of Ser409/410 of TDP-43 in FTLD-U and ALS. FEBS Lett 582(19):2899–2904

    Article  CAS  PubMed  Google Scholar 

  126. Neumann M (2009) Molecular neuropathology of TDP-43 proteinopathies. Int J Mol Sci 10(1):232–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Arai T et al (2010) Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy. Neuropathology 30(2):170–181

    Article  PubMed  Google Scholar 

  128. Herskowitz JH et al (2012) Asparaginyl endopeptidase cleaves TDP-43 in brain. Proteomics 12(15–16):2455–2463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Davidson Y et al (2007) Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113(5):521–533

    Article  CAS  PubMed  Google Scholar 

  130. Gitler AD, Shorter J (2011) RNA-binding proteins with prion-like domains in ALS and FTLD-U. Prion 5(3):179–187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Vance C et al (2013) ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules. Hum Mol Genet 22(13):2676–2688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Patel A et al (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162(5):1066–1077

    Article  CAS  PubMed  Google Scholar 

  133. Farrawell NE et al (2015) Distinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions. Sci Rep 5:13416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Woulfe J, Gray DA, Mackenzie IR (2010) FUS-immunoreactive intranuclear inclusions in neurodegenerative disease. Brain Pathol 20(3):589–597

    Article  CAS  PubMed  Google Scholar 

  135. Molliex A et al (2015) Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163(1):123–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Gendron TF et al (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126(6):829–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Su Z et al (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83(5):1043–1050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Mizielinska S et al (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345(6201):1192–1194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Freibaum BD et al (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525(7567):129–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Jovicic A et al (2015) Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18(9):1226–1229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wen X et al (2014) Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 84(6):1213–1225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kwon I et al (2014) Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345(6201):1139–1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19(8):983–997

    Article  CAS  PubMed  Google Scholar 

  144. Gorrie GH et al (2014) Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2. Proc Natl Acad Sci U S A 111(40):14524–14529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Ceballos-Diaz C et al (2015) Viral expression of ALS-linked ubiquilin-2 mutants causes inclusion pathology and behavioral deficits in mice. Mol Neurodegener 10:25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Brettschneider J et al (2012) Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol 123(6):825–839

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Fecto F et al (2011) SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 68(11):1440–1446

    Article  PubMed  Google Scholar 

  148. Lattante S et al (2015) Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD. Hum Mol Genet 24(6):1682–1690

    Article  CAS  PubMed  Google Scholar 

  149. Bucelli RC et al (2015) SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles. Neurology 85(8):665–674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Hocking LJ et al (2002) Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget’s disease. Hum Mol Genet 11(22):2735–2739

    Article  CAS  PubMed  Google Scholar 

  151. Benatar M et al (2013) Motor neuron involvement in multisystem proteinopathy: implications for ALS. Neurology 80(20):1874–1880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Tresse E et al (2010) VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6(2):217–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Freischmidt A et al (2015) Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 18(5):631–636

    Article  CAS  PubMed  Google Scholar 

  154. Ciura S et al (2013) Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol 74(2):180–187

    CAS  PubMed  Google Scholar 

  155. Koppers M et al (2015) C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann Neurol 78(3):426–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Fratta P et al (2013) Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. Acta Neuropathol 126(3):401–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Haeusler AR et al (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507(7491):195–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jiang H et al (2004) Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet 13(24):3079–3088

    Article  CAS  PubMed  Google Scholar 

  159. Kanadia RN et al (2003) A muscleblind knockout model for myotonic dystrophy. Science 302(5652):1978–1980

    Article  CAS  PubMed  Google Scholar 

  160. Xu Z et al (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A 110(19):7778–7783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Donnelly CJ et al (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80(2):415–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Lee JE, Cooper TA (2009) Pathogenic mechanisms of myotonic dystrophy. Biochem Soc Trans 37(Pt 6):1281–1286

    Article  CAS  PubMed  Google Scholar 

  163. Zhang K et al (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525(7567):56–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lagier-Tourenne C et al (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A 110(47):E4530–E4539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Gomez-Deza J et al (2015) Dipeptide repeat protein inclusions are rare in the spinal cord and almost absent from motor neurons in C9ORF72 mutant amyotrophic lateral sclerosis and are unlikely to cause their degeneration. Acta Neuropathol Commun 3(1):38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Gendron TF et al (2015) Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers. Acta Neuropathol 130(4):559–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Henneberry RC et al (1989) Neurotoxicity at the N-methyl-D-aspartate receptor in energy-compromised neurons. An hypothesis for cell death in aging and disease. Ann N Y Acad Sci 568:225–233

    Article  CAS  PubMed  Google Scholar 

  168. Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326(22):1464–1468

    Article  CAS  PubMed  Google Scholar 

  169. Bruijn LI et al (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18(2):327–338

    Article  CAS  PubMed  Google Scholar 

  170. Yang Y et al (2010) Epigenetic regulation of neuron-dependent induction of astroglial synaptic protein GLT1. Glia 58(3):277–286

    PubMed  PubMed Central  Google Scholar 

  171. Yang Y et al (2009) Presynaptic regulation of astroglial excitatory neurotransmitter transporter GLT1. Neuron 61(6):880–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kawahara Y et al (2004) Glutamate receptors: RNA editing and death of motor neurons. Nature 427(6977):801

    Article  CAS  PubMed  Google Scholar 

  173. Murakami T et al (2001) Impaired retrograde axonal transport of adenovirus-mediated E. coli LacZ gene in the mice carrying mutant SOD1 gene. Neurosci Lett 308(3):149–152

    Article  CAS  PubMed  Google Scholar 

  174. Perlson E et al (2009) A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration. J Neurosci 29(31):9903–9917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Song Y et al (2013) Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm. Proc Natl Acad Sci U S A 110(14):5428–5433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Figlewicz DA et al (1994) Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet 3(10):1757–1761

    Article  CAS  PubMed  Google Scholar 

  177. Tomkins J et al (1998) Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport 9(17):3967–3970

    Article  CAS  PubMed  Google Scholar 

  178. Al-Chalabi A et al (1999) Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. Hum Mol Genet 8(2):157–164

    Article  CAS  PubMed  Google Scholar 

  179. Leung CL et al (2004) A pathogenic peripherin gene mutation in a patient with amyotrophic lateral sclerosis. Brain Pathol 14(3):290–296

    Article  CAS  PubMed  Google Scholar 

  180. Corrado L et al (2011) A novel peripherin gene (PRPH) mutation identified in one sporadic amyotrophic lateral sclerosis patient. Neurobiol Aging 32(3):552e1–6

    Article  CAS  Google Scholar 

  181. Puls I et al (2003) Mutant dynactin in motor neuron disease. Nat Genet 33(4):455–456

    Article  CAS  PubMed  Google Scholar 

  182. Clement AM et al (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302(5642):113–117

    Article  CAS  PubMed  Google Scholar 

  183. Tong X et al (2014) Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice. Nat Neurosci 17(5):694–703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Yazawa I et al (2005) Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45(6):847–859

    Article  CAS  PubMed  Google Scholar 

  185. Custer SK et al (2006) Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat Neurosci 9(10):1302–1311

    Article  CAS  PubMed  Google Scholar 

  186. Nagai M et al (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Haidet-Phillips AM et al (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29(9):824–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Re DB et al (2014) Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 81(5):1001–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Richard JP, Maragakis NJ (2015) Induced pluripotent stem cells from ALS patients for disease modeling. Brain Res 1607:15–25

    Article  CAS  PubMed  Google Scholar 

  190. Sulston JE, Horvitz HR (1977) Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56(1):110–156

    Article  CAS  PubMed  Google Scholar 

  191. Howe K et al (2013) The zebrafish reference genome sequence and its relationship to the human genome. Nature 496(7446):498–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Gurney ME et al (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264(5166):1772–1775

    Article  CAS  PubMed  Google Scholar 

  193. Wong PC et al (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14(6):1105–1116

    Article  CAS  PubMed  Google Scholar 

  194. Fischer LR et al (2012) Absence of SOD1 leads to oxidative stress in peripheral nerve and causes a progressive distal motor axonopathy. Exp Neurol 233(1):163–171

    Article  CAS  PubMed  Google Scholar 

  195. Kostrominova TY (2010) Advanced age-related denervation and fiber-type grouping in skeletal muscle of SOD1 knockout mice. Free Radic Biol Med 49(10):1582–1593

    Article  CAS  PubMed  Google Scholar 

  196. Shefner JM et al (1999) Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy. Neurology 53(6):1239–1246

    Article  CAS  PubMed  Google Scholar 

  197. Boillee S et al (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312(5778):1389–1392

    Article  CAS  PubMed  Google Scholar 

  198. Lobsiger CS et al (2009) Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. Proc Natl Acad Sci U S A 106(11):4465–4470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Yamanaka K et al (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11(3):251–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Wang L et al (2012) Selective knockdown of mutant SOD1 in Schwann cells ameliorates disease in G85R mutant SOD1 transgenic mice. Neurobiol Dis 48(1):52–57

    Article  PubMed  CAS  Google Scholar 

  201. Wang L et al (2009) The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. Neurobiol Dis 35(2):234–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Kang SH et al (2013) Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 16(5):571–579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Wegorzewska I et al (2009) TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 106(44):18809–18814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Esmaeili MA et al (2013) Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis. Int J Exp Pathol 94(1):56–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Swarup V et al (2011) Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments. Brain 134(Pt 9):2610–2626

    Article  PubMed  Google Scholar 

  206. Philips T, Rothstein JD (2015) Rodent models of amyotrophic lateral sclerosis. Curr Protoc Pharmacol 69:5.67.1–5.67.21

    Google Scholar 

  207. McGoldrick P et al (2013) Rodent models of amyotrophic lateral sclerosis. Biochim Biophys Acta 1832(9):1421–1436

    Article  CAS  PubMed  Google Scholar 

  208. Da Cruz S, Cleveland DW (2011) Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr Opin Neurobiol 21(6):904–919

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Hukema RK et al (2014) A new inducible transgenic mouse model for C9orf72-associated GGGGCC repeat expansion supports a gain-of-function mechanism in C9orf72-associated ALS and FTD. Acta Neuropathol Commun 2:166

    Article  PubMed  PubMed Central  Google Scholar 

  210. Chew J et al (2015) Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348(6239):1151–1154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Takahashi K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872

    Article  CAS  PubMed  Google Scholar 

  212. Dimos JT et al (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321(5893):1218–1221

    Article  CAS  PubMed  Google Scholar 

  213. Amoroso MW et al (2013) Accelerated high-yield generation of limb-innervating motor neurons from human stem cells. J Neurosci 33(2):574–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Krencik R, Zhang SC (2011) Directed differentiation of functional astroglial subtypes from human pluripotent stem cells. Nat Protoc 6(11):1710–1717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Roybon L et al (2013) Human stem cell-derived spinal cord astrocytes with defined mature or reactive phenotypes. Cell Rep 4(5):1035–1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Haidet-Phillips AM et al (2014) Gene profiling of human induced pluripotent stem cell-derived astrocyte progenitors following spinal cord engraftment. Stem Cells Transl Med 3(5):575–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Ogawa S et al (2011) Induction of oligodendrocyte differentiation from adult human fibroblast-derived induced pluripotent stem cells. In Vitro Cell Dev Biol Anim 47(7):464–469

    Article  CAS  PubMed  Google Scholar 

  218. Wang S et al (2013) Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12(2):252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Liu Q et al (2012) Human neural crest stem cells derived from human ESCs and induced pluripotent stem cells: induction, maintenance, and differentiation into functional schwann cells. Stem Cells Transl Med 1(4):266–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Salani S et al (2012) Generation of skeletal muscle cells from embryonic and induced pluripotent stem cells as an in vitro model and for therapy of muscular dystrophies. J Cell Mol Med 16(7):1353–1364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Darabi R et al (2012) Human ES- and iPS-derived myogenic progenitors restore DYSTROPHIN and improve contractility upon transplantation in dystrophic mice. Cell Stem Cell 10(5):610–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Johns Hopkins University, 855 N. Wolfe St., Rm 248, Baltimore, MD, 21205, USA

    Hristelina Ilieva & Nicholas J. Maragakis M.D.

Authors
  1. Hristelina Ilieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas J. Maragakis M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicholas J. Maragakis M.D. .

Editor information

Editors and Affiliations

  1. University of Melbourne Florey Institute of Neuroscience and Mental Health, Parkville, Australia

    Philip Beart

  2. Pediatrics and Pharmacology Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael Robinson

  3. School of Life Sciences Bradford School of Pharmacy, University of Bradford, Bradford, United Kingdom

    Marcus Rattray

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Nicholas J. Maragakis

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Ilieva, H., Maragakis, N.J. (2017). Motoneuron Disease: Basic Science. In: Beart, P., Robinson, M., Rattray, M., Maragakis, N. (eds) Neurodegenerative Diseases. Advances in Neurobiology, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-57193-5_6

Download citation

Publish with us

Policies and ethics

Search

Navigation