Advertisement

CNS Drugs

, Volume 30, Issue 3, pp 227–243 | Cite as

Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis

  • Diane Moujalled
  • Anthony R. White
Review Article

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive adult-onset, neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. Over recent years, numerous genes ha ve been identified that promote disease pathology, including SOD1, TARDBP, and the expanded hexanucleotide repeat (GGGGCC) within C9ORF72. However, despite these major advances in identifying genes contributing to ALS pathogenesis, there remains only one currently approved therapeutic: the glutamate antagonist, riluzole. Seminal breakthroughs in the pathomechanisms and genetic factors associated with ALS have heavily relied on the use of rodent models that recapitulate the ALS phenotype; however, while many therapeutics have proved to be significant in animal models by prolonging life and rescuing motor deficits, they have failed in human clinical trials. This may be due to fundamental differences between rodent models and human disease, the fact that animal models are based on overexpression of mutated genes, and confounding issues such as difficulties mimicking the dosing schedules and regimens implemented in mouse models to humans. Here, we review the major pathways associated with the pathology of ALS, the rodent models engineered to test efficacy of candidate drugs, the advancements being made in stem cell therapy for ALS, and what strategies may be important to circumvent the lack of successful translational studies in the clinic.

Keywords

Amyotrophic Lateral Sclerosis Motor Neuron Amyotrophic Lateral Sclerosis Patient Riluzole Mutant SOD1 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with Ethical Standards

Funding

DM is supported by an Alzheimer’s Australia Dementia Research fellowship (AADRF) and funding from the Motor Neuron Disease Research Institute of Australia (MNDRIA). ARW is supported by an Australian Research Council Future Fellowship and The National Health and Medical Research Council of Australia.

Conflict of interest

Patent protection has previously been sought by the University of Melbourne for the use of bis(thiosemicarbazones) for treatment of diseases. ARW is a co-inventor on the patent application PCT/AU2007/001792 that is the subject of a commercialization contract between the University and a private company. The company has neither funded nor contributed to research described in this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

References

  1. 1.
    Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci. 2013;14(4):248–64. doi: 10.1038/Nrn3430.PubMedCrossRefGoogle Scholar
  2. 2.
    Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942–55. doi: 10.1016/S0140-6736(10)61156-7.PubMedCrossRefGoogle Scholar
  3. 3.
    Wood LK, Langford SJ. Motor neuron disease: a chemical perspective. J Med Chem. 2014;57(15):6316–31. doi: 10.1021/jm5001584.PubMedCrossRefGoogle Scholar
  4. 4.
    Joyce PI, Fratta P, Fisher EM, Acevedo-Arozena A. SOD1 and TDP-43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments. Mamm Genome. 2011;22(7–8):420–48. doi: 10.1007/s00335-011-9339-1.PubMedCrossRefGoogle Scholar
  5. 5.
    Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011;7(11):603–15. doi: 10.1038/nrneurol.2011.150.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosen DR. Mutations in Cu/Zn superoxide-dismutase gene are associated with familial amyotrophic-lateral-sclerosis. Nature. 1993;364(6435):362.PubMedGoogle Scholar
  7. 7.
    Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung WY, et al. Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science. 1993;261(5124):1047–51.PubMedCrossRefGoogle Scholar
  8. 8.
    Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319(5870):1668–72. doi: 10.1126/Science.1154584.PubMedCrossRefGoogle Scholar
  9. 9.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245–56. doi: 10.1016/J.Neuron.2011.09.011.
  10. 10.
    Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257–68. doi: 10.1016/J.Neuron.2011.09.010.
  11. 11.
    Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013;339(6125):1335–8. doi: 10.1126/science.1232927.PubMedCrossRefGoogle Scholar
  12. 12.
    Bryson HM, Fulton B, Benfield P. Riluzole: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis. Drugs. 1996;52(4):549–63.PubMedCrossRefGoogle Scholar
  13. 13.
    Fontana AC. Current approaches to enhance glutamate transporter function and expression. J Neurochem. 2015. doi: 10.1111/jnc.13200.Google Scholar
  14. 14.
    Peng S, Zhang Y, Zhang J, Wang H, Ren B. Glutamate receptors and signal transduction in learning and memory. Mol Biol Rep. 2011;38(1):453–60. doi: 10.1007/s11033-010-0128-9.PubMedCrossRefGoogle Scholar
  15. 15.
    Soni N, Reddy BV, Kumar P. GLT-1 transporter: an effective pharmacological target for various neurological disorders. Pharmacol Biochem Behav. 2014;127:70–81. doi: 10.1016/j.pbb.2014.10.001.PubMedCrossRefGoogle Scholar
  16. 16.
    Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol. 2011;7(11):616–30. doi: 10.1038/nrneurol.2011.152.PubMedCrossRefGoogle Scholar
  17. 17.
    Van Damme P, Dewil M, Robberecht W, Van Den Bosch L. Excitotoxicity and amyotrophic lateral sclerosis. Neurodegener Dis. 2005;2(3–4):147–59. doi: 10.1159/000089620.PubMedCrossRefGoogle Scholar
  18. 18.
    Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16(3):675–86.PubMedCrossRefGoogle Scholar
  19. 19.
    Guo Y, Duan W, Li Z, Huang J, Yin Y, Zhang K, et al. Decreased GLT-1 and increased SOD1 and HO-1 expression in astrocytes contribute to lumbar spinal cord vulnerability of SOD1-G93A transgenic mice. FEBS Lett. 2010;584(8):1615–22. doi: 10.1016/j.febslet.2010.03.025.PubMedCrossRefGoogle Scholar
  20. 20.
    Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 1995;38(1):73–84. doi: 10.1002/ana.410380114.PubMedCrossRefGoogle Scholar
  21. 21.
    Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral Scler. 2003;4(3):191–206.Google Scholar
  22. 22.
    Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005;433(7021):73–7. doi: 10.1038/nature03180.PubMedCrossRefGoogle Scholar
  23. 23.
    Beghi E, Bendotti C, Mennini T. New ideas for therapy in ALS: critical considerations. Amyotroph Lateral Scler. 2006;7(2):126–7 (discussion 7). doi: 10.1080/14660820510012040.
  24. 24.
    Cudkowicz M, Bozik ME, Ingersoll EW, Miller R, Mitsumoto H, Shefner J, et al. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med. 2011;17(12):1652–6. doi: 10.1038/Nm.2579.PubMedCrossRefGoogle Scholar
  25. 25.
    Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, et al. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler. 2008;9(1):4–15. doi: 10.1080/17482960701856300.PubMedCrossRefGoogle Scholar
  26. 26.
    Turner MR, Bowser R, Bruijn L, Dupuis L, Ludolph A, McGrath M, et al. Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14(Suppl 1):19–32. doi: 10.3109/21678421.2013.778554.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Shaw PJ, Ince PG, Falkous G, Mantle D. Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol. 1995;38(4):691–5. doi: 10.1002/ana.410380424.PubMedCrossRefGoogle Scholar
  28. 28.
    Ferrante RJ, Browne SE, Shinobu LA, Bowling AC, Baik MJ, MacGarvey U, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem. 1997;69(5):2064–74.PubMedCrossRefGoogle Scholar
  29. 29.
    Smith RG, Henry YK, Mattson MP, Appel SH. Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Ann Neurol. 1998;44(4):696–9. doi: 10.1002/ana.410440419.PubMedCrossRefGoogle Scholar
  30. 30.
    Shibata N, Nagai R, Uchida K, Horiuchi S, Yamada S, Hirano A, et al. Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients. Brain Res. 2001;917(1):97–104.PubMedCrossRefGoogle Scholar
  31. 31.
    Kiskinis E, Sandoe J, Williams LA, Boulting GL, Moccia R, Wainger BJ, et al. Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell. 2014;14(6):781–95. doi: 10.1016/j.stem.2014.03.004.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Chang Y, Kong Q, Shan X, Tian G, Ilieva H, Cleveland DW, et al. Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS. PLoS One. 2008;3(8):e2849. doi: 10.1371/journal.pone.0002849.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Sarlette A, Krampfl K, Grothe C, Neuhoff N, Dengler R, Petri S. Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2008;67(11):1055–62. doi: 10.1097/NEN.0b013e31818b4906.PubMedCrossRefGoogle Scholar
  34. 34.
    Petri S, Korner S, Kiaei M. Nrf2/ARE signaling pathway: key mediator in oxidative stress and potential therapeutic target in ALS. Neurol Res Int. 2012;2012:878030. doi: 10.1155/2012/878030.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Neymotin A, Calingasan NY, Wille E, Naseri N, Petri S, Damiano M, et al. Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radical Biol Med. 2011;51(1):88–96. doi: 10.1016/j.freeradbiomed.2011.03.027.CrossRefGoogle Scholar
  36. 36.
    Andreassen OA, Dedeoglu A, Klivenyi P, Beal MF, Bush AI. N-Acetyl-l-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. NeuroReport. 2000;11(11):2491–3.PubMedCrossRefGoogle Scholar
  37. 37.
    Orrell RW, Lane RJM, Ross M. A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease. Amyotroph Lateral Scler. 2008;9(4):195–211. doi: 10.1080/17482960801900032.PubMedCrossRefGoogle Scholar
  38. 38.
    Louwerse ES, Weverling GJ, Bossuyt PMM, Meyjes FEP, Dejong JMBV. Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic-lateral-sclerosis. Arch Neurol. 1995;52(6):559–64.PubMedCrossRefGoogle Scholar
  39. 39.
    Crow JP, Calingasan NY, Chen JY, Hill JL, Beal MF. Manganese porphyrin given at symptom onset markedly extends survival of ALS mice. Ann Neurol. 2005;58(2):258–65. doi: 10.1002/Ana.20552.PubMedCrossRefGoogle Scholar
  40. 40.
    Orrell RW, Lane RJ, Ross M. Antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2007(1):CD002829. doi: 10.1002/14651858.CD002829.pub4.
  41. 41.
    Pastula DM, Moore DH, Bedlack RS. Creatine for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2010(6). doi: 10.1002/14651858.Cd005225.Pub2.
  42. 42.
    Kwiecinski H, Janik P, Jamrozik Z, Opuchlik A. The effect of selegiline and vitamin E in the treatment of ALS: an open randomized clinical trials. Neurol Neurochir Pol. 2001;35(1 Suppl):101–6.PubMedGoogle Scholar
  43. 43.
    Benatar M. Lost in translation: treatment trials in the SOD1 mouse and in human ALS. Neurobiol Dis. 2007;26(1):1–13. doi: 10.1016/j.nbd.2006.12.015.PubMedCrossRefGoogle Scholar
  44. 44.
    Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radical Biol Med. 2010;48(5):629–41. doi: 10.1016/j.freeradbiomed.2009.11.018.CrossRefGoogle Scholar
  45. 45.
    Barber SC, Mead RJ, Shaw PJ. Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta. 2006;1762(11–12):1051–67. doi: 10.1016/J.Bbadis.2006.03.008.
  46. 46.
    Miquel E, Cassina A, Martinez-Palma L, Souza JM, Bolatto C, Rodriguez-Bottero S, et al. Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis. Free Radical Bio Med. 2014;2014(70):204–13. doi: 10.1016/J.Freeradbiomed.02.019.CrossRefGoogle Scholar
  47. 47.
    Nanou A, Higginbottom A, Valori CF, Wyles M, Ning K, Shaw P, et al. Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis. Mol Ther. 2013;21(8):1486–96. doi: 10.1038/Mt.2013.115.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Wiedemann FR, Manfredi G, Mawrin C, Beal MF, Schon EA. Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J Neurochem. 2002;80(4):616–25.PubMedCrossRefGoogle Scholar
  49. 49.
    Dhaliwal GK, Grewal RP. Mitochondrial DNA deletion mutation levels are elevated in ALS brains. NeuroReport. 2000;11(11):2507–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Ferri A, Cozzolino M, Crosio C, Nencini M, Casciati A, Gralla EB, et al. Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. Proc Natl Acad Sci. 2006;103(37):13860–5. doi: 10.1073/Pnas.0605814103.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Kirkinezos IG, Bacman SR, Hernandez D, Cossio JO, Arias LJ, Perez-Pinzon MA, et al. Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice. J Neurosci. 2005;25(1):164–72. doi: 10.1523/Jneurosci.3829-04.2005.PubMedCrossRefGoogle Scholar
  52. 52.
    Pandya RS, Zhu HN, Li W, Bowser R, Friedlander RM, Wang X. Therapeutic neuroprotective agents for amyotrophic lateral sclerosis. Cell Mol Life Sci. 2013;70(24):4729–45. doi: 10.1007/S00018-013-1415-0.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Wang WZ, Li L, Lin WL, Dickson DW, Petrucelli L, Zhang T, et al. The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Hum Mol Genet. 2013;22(23):4706–19. doi: 10.1093/Hmg/Ddt319.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Xu YF, Gendron TF, Zhang YJ, Lin WL, D’Alton S, Sheng H, et al. Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci. 2010;30(32):10851–9. doi: 10.1523/Jneurosci.1630-10.2010.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Bordet T, Buisson B, Michaud M, Drouot C, Galea P, Delaage P, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007;322(2):709–20. doi: 10.1124/Jpet.107.123000.PubMedCrossRefGoogle Scholar
  56. 56.
    Lenglet T, Lacomblez L, Abitbol JL, Ludolph A, Mora JS, Robberecht W, et al. A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis. Eur J Neurol. 2014;21(3):529–36. doi: 10.1111/Ene.12344.PubMedCrossRefGoogle Scholar
  57. 57.
    Genc B, Ozdinler PH. Moving forward in clinical trials for ALS: motor neurons lead the way please. Drug Discov Today. 2014;19(4):441–9. doi: 10.1016/j.drudis.2013.10.014.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992;140(3):691–707.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Zhang RZ, Gascon R, Miller RG, Gelinas DF, Mass J, Lancero M, et al. MCP-1 chemokine receptor CCR2 is decreased on circulating monocytes in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2006;179(1–2):87–93. doi: 10.1016/J.Jneuroim.2006.06.008.
  60. 60.
    Zhang R, Miller RG, Gascon R, Champion S, Katz J, Lancero M, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2009;206(1–2):121–4. doi: 10.1016/J.Jneuroim.2008.09.017.
  61. 61.
    Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, et al. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci. 2008;105(46):17913–8. doi: 10.1073/pnas.0804610105.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Beers DR, Henkel JS, Zhao W, Wang J, Appel SH. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci. 2008;105(40):15558–63. doi: 10.1073/pnas.0807419105.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918–34. doi: 10.1016/J.Cell.2010.02.016.
  64. 64.
    Kriz J, Nguyen MD, Julien JP. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2002;10(3):268–78.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002;417(6884):74–8. doi: 10.1038/417074a.PubMedCrossRefGoogle Scholar
  66. 66.
    Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 2007;6(12):1045–53. doi: 10.1016/S1474-4422(07)70270-3.PubMedCrossRefGoogle Scholar
  67. 67.
    Gamez J. Minocycline for the treatment of amyotrophic lateral sclerosis: neuroprotector or neurotoxin? Reflections on another failure of translational medicine. Neurologia. 2008;23(8):484–93.PubMedGoogle Scholar
  68. 68.
    Drachman DB, Frank K, Dykes-Hoberg M, Teismann P, Almer G, Przedborski S, et al. Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann Neurol. 2002;52(6):771–8. doi: 10.1002/ana.10374.PubMedCrossRefGoogle Scholar
  69. 69.
    Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol. 2006;60(1):22–31. doi: 10.1002/ana.20903.PubMedCrossRefGoogle Scholar
  70. 70.
    Koza P. RNA processing TDP-43 protein has a main pathological role in FTLD and ALS. Postepy Biochem. 2015;61(2):159–67.PubMedGoogle Scholar
  71. 71.
    Arnold ES, Ling SC, Huelga SC, Lagier-Tourenne C, Polymenidou M, Ditsworth D, 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. 2013;110(8):E736–45. doi: 10.1073/pnas.1222809110.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205–8. doi: 10.1126/science.1166066.PubMedCrossRefGoogle Scholar
  73. 73.
    Philips T, Rothstein JD. Rodent models of amyotrophic lateral sclerosis. Curr Protoc Pharmacol. 2015;69:5.67.1–5.67.21. doi: 10.1002/0471141755.ph0567s69.
  74. 74.
    Chew J, Gendron TF, Prudencio M, Sasaguri H, Zhang YJ, Castanedes-Casey M, et al. Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science. 2015;348(6239):1151–4. doi: 10.1126/science.aaa9344.
  75. 75.
    Hirano M, Quinzii CM, Mitsumoto H, Hays AP, Roberts JK, Richard P, et al. Senataxin mutations and amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2011;12(3):223–7. doi: 10.3109/17482968.2010.545952.PubMedCrossRefGoogle Scholar
  76. 76.
    Fecto F, Yan J, Vemula SP, Liu E, Yang Y, Chen W, et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol. 2011;68(11):1440–6. doi: 10.1001/archneurol.2011.250.PubMedCrossRefGoogle Scholar
  77. 77.
    Matus S, Valenzuela V, Medinas DB, Hetz C. ER dysfunction and protein folding stress in ALS. Int J Cell Biol. 2013;2013:674751. doi: 10.1155/2013/674751.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011;477(7363):211–5. doi: 10.1038/nature10353.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995;14(6):1105–16.PubMedCrossRefGoogle Scholar
  80. 80.
    Majcher V, Goode A, James V, Layfield R. Autophagy receptor defects and ALS-FTLD. Mol Cell Neurosci. 2015;66(Pt A):43–52. doi: 10.1016/j.mcn.2015.01.002.
  81. 81.
    Chen S, Sayana P, Zhang X, Le W. Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener. 2013;8:28. doi: 10.1186/1750-1326-8-28.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012;488(7412):499–503. doi: 10.1038/nature11280.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010;68(5):857–64. doi: 10.1016/j.neuron.2010.11.036.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004;75(5):822–31. doi: 10.1086/425287.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Wu D, Yu W, Kishikawa H, Folkerth RD, Iafrate AJ, Shen Y, et al. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol. 2007;62(6):609–17. doi: 10.1002/ana.21221.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Gurney ME, Cutting FB, Zhai P, Doble A, Taylor CP, Andrus PK, et al. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol. 1996;39(2):147–57. doi: 10.1002/ana.410390203.PubMedCrossRefGoogle Scholar
  87. 87.
    Van Damme P, Leyssen M, Callewaert G, Robberecht W, Van Den Bosch L. The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis. Neurosci Lett. 2003;343(2):81–4.PubMedCrossRefGoogle Scholar
  88. 88.
    Pascuzzi RM, Shefner J, Chappell AS, Bjerke JS, Tamura R, Chaudhry V, et al. A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010;11(3):266–71. doi: 10.3109/17482960903307805.PubMedCrossRefGoogle Scholar
  89. 89.
    Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med. 1999;5(3):347–50. doi: 10.1038/6568.PubMedCrossRefGoogle Scholar
  90. 90.
    Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. Minocycline delays disease onset and mortality in a transgenic model of ALS. NeuroReport. 2002;13(8):1067–70.CrossRefGoogle Scholar
  91. 91.
    Ittner A, Bertz J, Suh LS, Stevens CH, Gotz J, Ittner LM. Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice. J Neurochem. 2015;132(1):135–45. doi: 10.1111/jnc.12821.PubMedCrossRefGoogle Scholar
  92. 92.
    Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human Cu. Zn superoxide dismutase mutation. Science. 1994;264(5166):1772–5.PubMedCrossRefGoogle Scholar
  93. 93.
    Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, 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.PubMedCrossRefGoogle Scholar
  94. 94.
    Heiman-Patterson TD, Sher RB, Blankenhorn EA, Alexander G, Deitch JS, Kunst CB, et al. 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(2):79–86. doi: 10.3109/17482968.2010.550626.PubMedCrossRefGoogle Scholar
  95. 95.
    Mancuso R, Olivan S, Rando A, Casas C, Osta R, Navarro X. Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. Neurotherapeutics. 2012;9(4):814–26. doi: 10.1007/s13311-012-0140-y.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Acevedo-Arozena A, Kalmar B, Essa S, Ricketts T, Joyce P, Kent R, et al. A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis. Dis Models Mech. 2011;4(5):686–700. doi: 10.1242/dmm.007237.CrossRefGoogle Scholar
  97. 97.
    McGoldrick P, Joyce PI, Fisher EM, Greensmith L. Rodent models of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2013;1832(9):1421–36. doi: 10.1016/j.bbadis.2013.03.012.PubMedCrossRefGoogle Scholar
  98. 98.
    Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, 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. doi: 10.1016/j.bbrc.2006.10.093.PubMedCrossRefGoogle Scholar
  99. 99.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130–3. doi: 10.1126/science.1134108.PubMedCrossRefGoogle Scholar
  100. 100.
    Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci. 2009;106(44):18809–14. doi: 10.1073/pnas.0908767106.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Guo Y, Wang Q, Zhang K, An T, Shi P, Li Z, et al. HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice. Brain Res. 2012;1460:88–95. doi: 10.1016/j.brainres.2012.04.003.PubMedCrossRefGoogle Scholar
  102. 102.
    Esmaeili MA, Panahi M, Yadav S, Hennings L, Kiaei M. 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. 2013;94(1):56–64. doi: 10.1111/iep.12006.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Xu YF, Zhang YJ, Lin WL, Cao X, Stetler C, Dickson DW, et al. Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice. Mol Neurodegener. 2011;6:73. doi: 10.1186/1750-1326-6-73.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Swarup V, Phaneuf D, Bareil C, Robertson J, Rouleau GA, Kriz J, et al. Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments. Brain. 2011;134(Pt 9):2610–26. doi: 10.1093/brain/awr159.PubMedCrossRefGoogle Scholar
  105. 105.
    Liu YC, Chiang PM, Tsai KJ. Disease animal models of TDP-43 proteinopathy and their pre-clinical applications. Int J Mol Sci. 2013;14(10):20079–111. doi: 10.3390/ijms141020079.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci. 2010;107(8):3858–63. doi: 10.1073/pnas.0912417107.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Janssens J, Wils H, Kleinberger G, Joris G, Cuijt I, Ceuterick-de Groote C, et al. Overexpression of ALS-associated p. M337V human TDP-43 in mice worsens disease features compared to wild-type human TDP-43 mice. Mol Neurobiol. 2013;48(1):22–35. doi: 10.1007/s12035-013-8427-5.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Tsai KJ, Yang CH, Fang YH, Cho KH, Chien WL, Wang WT, et al. Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J Exp Med. 2010;207(8):1661–73. doi: 10.1084/jem.20092164.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Mackenzie IR, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010;9(10):995–1007. doi: 10.1016/S1474-4422(10)70195-2.PubMedCrossRefGoogle Scholar
  110. 110.
    Mitchell JC, McGoldrick P, Vance C, Hortobagyi T, Sreedharan J, Rogelj B, et al. Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol. 2013;125(2):273–88. doi: 10.1007/s00401-012-1043-z.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Verbeeck C, Deng Q, Dejesus-Hernandez M, Taylor G, Ceballos-Diaz C, Kocerha J, et al. Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis. Mol Neurodegener. 2012;7:53. doi: 10.1186/1750-1326-7-53.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Huang C, Zhou H, Tong J, Chen H, Liu YJ, Wang D, et al. FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet. 2011;7(3):e1002011. doi: 10.1371/journal.pgen.1002011.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Huang C, Tong J, Bi F, Wu Q, Huang B, Zhou H, et al. Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats. Hum Mol Genet. 2012;21(21):4602–14. doi: 10.1093/hmg/dds299.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Almeida S, Gascon E, Tran H, Chou HJ, Gendron TF, Degroot 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. doi: 10.1007/s00401-013-1149-y.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Hukema RK, Riemslagh FW, Melhem S, van der Linde HC, Severijnen LA, Edbauer D, et al. 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. 2014;2:166. doi: 10.1186/s40478-014-0166-y.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, Vidensky S, et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron. 2013;80(2):415–28. doi: 10.1016/j.neuron.2013.10.015.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Thomsen GM, Gowing G, Svendsen S, Svendsen CN. The past, present and future of stem cell clinical trials for ALS. Exp Neurol. 2014;262 Pt B:127–37. doi: 10.1016/j.expneurol.2014.02.021.
  118. 118.
    Zhao CP, Zhang C, Zhou SN, Xie YM, Wang YH, Huang H, et al. Human mesenchymal stromal cells ameliorate the phenotype of SOD1-G93A ALS mice. Cytotherapy. 2007;9(5):414–26. doi: 10.1080/14653240701376413.PubMedCrossRefGoogle Scholar
  119. 119.
    Mazzini L, Ferrero I, Luparello V, Rustichelli D, Gunetti M, Mareschi K, et al. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a Phase I clinical trial. Exp Neurol. 2010;223(1):229–37. doi: 10.1016/j.expneurol.2009.08.007.PubMedCrossRefGoogle Scholar
  120. 120.
    Mazzini L, Mareschi K, Ferrero I, Miglioretti M, Stecco A, Servo S, et al. Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study. Cytotherapy. 2012;14(1):56–60. doi: 10.3109/14653249.2011.613929.PubMedCrossRefGoogle Scholar
  121. 121.
    Xu L, Shen P, Hazel T, Johe K, Koliatsos VE. Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 transgenic rats. Neurosci Lett. 2011;494(3):222–6. doi: 10.1016/j.neulet.2011.03.017.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Feldman EL, Boulis NM, Hur J, Johe K, Rutkove SB, Federici T, et al. Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol. 2014;75(3):363–73. doi: 10.1002/ana.24113.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science. 2008;321(5893):1218–21. doi: 10.1126/science.1158799.PubMedCrossRefGoogle Scholar
  124. 124.
    Ferraiuolo L. The non-cell-autonomous component of ALS: new in vitro models and future challenges. Biochem Soc Trans. 2014;42(5):1270–4. doi: 10.1042/BST20140168.PubMedCrossRefGoogle Scholar
  125. 125.
    Bilican B, Serio A, Barmada SJ, Nishimura AL, Sullivan GJ, Carrasco M, et al. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci. 2012;109(15):5803–8. doi: 10.1073/pnas.1202922109.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Saporta MA, Grskovic M, Dimos JT. Induced pluripotent stem cells in the study of neurological diseases. Stem Cell Res Ther. 2011;2(5):37. doi: 10.1186/scrt78.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Ittner LM, Halliday GM, Kril JJ, Gotz J, Hodges JR, Kiernan MC. FTD and ALS-translating mouse studies into clinical trials. Nat Rev Neurol. 2015;11(6):360–6. doi: 10.1038/nrneurol.2015.65.PubMedCrossRefGoogle Scholar
  128. 128.
    Lietner M, Menzies S, Cutz C. Working with ALS mice: guidelines for preclinical testing and colony management. In: PRIZE4LIFE, The Jackson Laboratory; 2009.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Pathology and Florey Institute of Neuroscience and Mental HealthThe University of MelbourneMelbourneAustralia

Personalised recommendations