Rodent Models of Amyotrophic Lateral Sclerosis

Thomas Philips1, Jeffrey D. Rothstein1

1 Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, Maryland
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.67
DOI:  10.1002/0471141755.ph0567s69
Online Posting Date:  June, 2015
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Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the central nervous system. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3 to 5 years after disease onset. The condition may be familial (fALS 10%) or sporadic ALS (sALS, 90%). The large majority of fALS cases are due to genetic mutations in the Superoxide dismutase 1 gene (SOD1, 15% of fALS) and repeat nucleotide expansions in the gene encoding C9ORF72 (∼40% to 50% of fALS and ∼10% of sALS). Studies suggest that ALS is mediated through aberrant protein homeostasis (i.e., ER stress and autophagy) and/or changes in RNA processing (as in all non‐SOD1‐mediated ALS). In all of these cases, animal models suggest that the disorder is mediated non‐cell autonomously, i.e., not only motor neurons are involved, but glial cells including microglia, astrocytes, and oligodendrocytes, and other neuronal subpopulations are also implicated in the pathogenesis. Provided in this unit is a review of ALS rodent models, including discussion of their relative advantages and disadvantages. Emphasis is placed on correlating the model phenotype with the human condition and the utility of the model for defining the disease process. Information is also presented on RNA processing studies in ALS research, with particular emphasis on the newest ALS rodent models. © 2015 by John Wiley & Sons, Inc.

Keywords: Amyotrophic Lateral Sclerosis; RNA processing alterations; rodent models; motor neuron; glia; aberrant protein homeostasis

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Table of Contents

  • Introduction
  • Early Animal Models of ALS, Mutations in SOD1 Paved the Way
  • ALS as a Disease of Aberrant RNA Processing: The Need for New ALS Mouse Models
  • Aberrant RNA Processing Contributing to ALS: The Development of TDP‐43 Transgenic Mouse Models
  • Major Caveats of TDP‐43 Transgenic Rodent Models
  • Other Rodent Models Expressing Different ALS‐Causing Mutations
  • Future Perspectives
  • Acknowledgements
  • Literature Cited
  • Tables
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Literature Cited

Literature Cited
  Alfieri, J.A., Pino, N.S., and Igaz, L.M. 2014. Reversible behavioral phenotypes in a conditional mouse model of TDP‐43 proteinopathies. J. Neurosci. 34:15244‐15259.
  Arnold, E.S., Ling, S.C., Huelga, S.C., Lagier‐Tourenne, C., Polymenidou, M., Ditsworth, D., Kordasiewicz, H.B., McAlonis‐Downes, M., Platoshyn, O., Parone, P.A., Da Cruz, S., Clutario, K.M., Swing, D., Tessarollo, L., Marsala, M., Shaw, C.E., Yeo, G.W., and Cleveland, D.W. 2013. 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. 110:E736‐E745.
  Beck, M., Flachenecker, P., Magnus, T., Giess, R., Reiners, K., Toyka, K.V., and Naumann, M. 2005. Autonomic dysfunction in ALS: A preliminary study on the effects of intrathecal BDNF. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 6:100‐103.
  Beers, D.R., Henkel, J.S., Xiao, Q., Zhao, W., Wang, J., Yen, A.A., Siklos, L., McKercher, S.R., and Appel, S.H. 2006. Wild‐type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. U.S.A. 103:16021‐16026.
  Bendotti, C., Tortarolo, M., Suchak, S.K., Calvaresi, N., Carvelli, L., Bastone, A., Rizzi, M., Rattray, M., and Mennini, T. 2001. Transgenic SOD1 G93A mice develop reduced GLT‐1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. J. Neurochem. 79:737‐746.
  Bensimon, G., Lacomblez, L., and Meininger, V. 1994. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N. Engl. J. Med. 330:585‐591.
  Boillee, S., Vande Velde, C., and Cleveland, D.W. 2006a. ALS: A disease of motor neurons and their nonneuronal neighbors. Neuron 52:39‐59.
  Boillee, S., Yamanaka, K., Lobsiger, C.S., Copeland, N.G., Jenkins, N.A., Kassiotis, G., Kollias, G., and Cleveland, D.W. 2006b. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389‐1392.
  Borchelt, D.R. and Sisodia, S.S. 1996. Loss of functional prion protein: A role in prion disorders? Chem. Biol. 3:619‐621.
  Bruijn, L.I., Becher, M.W., Lee, M.K., Anderson, K.L., Jenkins, N.A., Copeland, N.G., Sisodia, S.S., Rothstein, J.D., Borchelt, D.R., Price, D.L., and Cleveland, D.W. 1997. ALS‐linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1‐containing inclusions. Neuron 18:327‐338.
  Caccamo, A., Majumder, S., and Oddo, S. 2012. Cognitive decline typical of frontotemporal lobar degeneration in transgenic mice expressing the 25‐kDa C‐terminal fragment of TDP‐43. Am. J. Pathol. 180:293‐302.
  Cannon, A., Yang, B., Knight, J., Farnham, I.M., Zhang, Y., Wuertzer, C.A., D'Alton, S., Lin, W.L., Castanedes‐Casey, M., Rousseau, L., Scott, B., Jurasic, M., Howard, J., Yu, X., Bailey, R., Sarkisian, M.R., Dickson, D.W., Petrucelli, L., and Lewis, J. 2012. Neuronal sensitivity to TDP‐43 overexpression is dependent on timing of induction. Acta Neuropathol. 123:807‐823.
  Chen, Y.Z., Bennett, C.L., Huynh, H.M., Blair, I.P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M.L., Rabin, B.A., Nicholson, G.A., Auer‐Grumbach, M., Wagner, K., De Jonghe, P., Griffin, J.W., Fischbeck, K.H., Timmerman, V., Cornblath, D.R., and Chance, P.F. 2004. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74:1128‐1135.
  Chiang, P.M., Ling, J., Jeong, Y.H., Price, D.L., Aja, S.M., and Wong, P.C. 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. 107:16320‐16324.
  Chou, S.M., Wang, H.S., and Komai, K. 1996. Colocalization of NOS and SOD1 in neurofilament accumulation within motor neurons of amyotrophic lateral sclerosis: an immunohistochemical study. J. Chem. Neuroanat. 10:249‐258.
  Clement, A.M., Nguyen, M.D., Roberts, E.A., Garcia, M.L., Boillee, S., Rule, M., McMahon, A.P., Doucette, W., Siwek, D., Ferrante, R.J., Brown, R.H. Jr., Julien, J.P., Goldstein, L.S., and Cleveland, D.W. 2003. Wild‐type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113‐117.
  Cudkowicz, M.E., Shefner, J.M., Schoenfeld, D.A., Zhang, H., Andreasson, K.I., Rothstein, J.D., and Drachman, D.B. 2006. Trial of celecoxib in amyotrophic lateral sclerosis. Ann. Neurol. 60:22‐31.
  Dal Canto, M.C. and Gurney, M.E. 1994. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am. J. Pathol. 145:1271‐1279.
  Dayton, R.D., Gitcho, M.A., Orchard, E.A., Wilson, J.D., Wang, D.B., Cain, C.D., Johnson, J.A., Zhang, Y.J., Petrucelli, L., Mathis, J.M., and Klein, R.L. 2013. Selective forelimb impairment in rats expressing a pathological TDP‐43 25 kDa C‐terminal fragment to mimic amyotrophic lateral sclerosis. Mol. Ther. 21:1324‐1334.
  DeJesus‐Hernandez, M., Mackenzie, I.R., Boeve, B.F., Boxer, A.L., Baker, M., Rutherford, N.J., Nicholson, A.M., Finch, N.A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., Sengdy, P., Hsiung, G.Y., Karydas, A., Seeley, W.W., Josephs, K.A., Coppola, G., Geschwind, D.H., Wszolek, Z.K., Feldman, H., Knopman, D.S., Petersen, R.C., Miller, B.L., Dickson, D.W., Boylan, K.B., Graff‐Radford, N.R., and Rademakers, R. 2011. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p‐linked FTD and ALS. Neuron 72:245‐256.
  Deng, H.X., Shi, Y., Furukawa, Y., Zhai, H., Fu, R., Liu, E., Gorrie, G.H., Khan, M.S., Hung, W.Y., Bigio, E.H., Lukas, T., Dal Canto, M.C., O'Halloran, T.V., and Siddique, T. 2006. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc. Natl. Acad. Sci. U.S.A. 103:7142‐7147.
  Deng, H.X., Chen, W., Hong, S.T., Boycott, K.M., Gorrie, G.H., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G.H., Donkervoort, S., Bigio, E.H., Brooks, B.R., Ajroud, K., Sufit, R.L., Haines, J.L., Mugnaini, E., Pericak‐Vance, M.A., and Siddique, T. 2011. Mutations in UBQLN2 cause dominant X‐linked juvenile and adult‐onset ALS and ALS/dementia. Nature 477:211‐215.
  Dimos, J.T., Rodolfa, K.T., Niakan, K.K., Weisenthal, L.M., Mitsumoto, H., Chung, W., Croft, G.F., Saphier, G., Leibel, R., Goland, R., Wichterle, H., Henderson, C.E., and Eggan, K. 2008. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321:1218‐1221.
  Donnelly, C.J., Zhang, P.W., Pham, J.T., Haeusler, A.R., Mistry, N.A., Vidensky, S., Daley, E.L., Poth, E.M., Hoover, B., Fines, D.M., Maragakis, N., Tienari, P.J., Petrucelli, L., Traynor, B.J., Wang, J., Rigo, F., Bennett, C.F., Blackshaw, S., Sattler, R., and Rothstein, J.D. 2013. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80:415‐428.
  Fecto, F., Yan, J., Vemula, S.P., Liu, E., Yang, Y., Chen, W., Zheng, J.G., Shi, Y., Siddique, N., Arrat, H., Donkervoort, S., Ajroud‐Driss, S., Sufit, R.L., Heller, S.L., Deng, H.X., and Siddique, T. 2011. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68:1440‐1446.
  Fischer, L.R., Culver, D.G., Tennant, P., Davis, A.A., Wang, M., Castellano‐Sanchez, A., Khan, J., Polak, M.A., and Glass, J.D. 2004. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp. Neurol. 185:232‐240.
  Gong, Y.H., Parsadanian, A.S., Andreeva, A., Snider, W.D., and Elliott, J.L. 2000. Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J. Neurosci. 20:660‐665.
  Gordon, P.H., Moore, D.H., Miller, R.G., Florence, J.M., Verheijde, J.L., Doorish, C., Hilton, J.F., Spitalny, G.M., MacArthur, R.B., Mitsumoto, H., Neville, H.E., Boylan, K., Mozaffar, T., Belsh, J.M., Ravits, J., Bedlack, R.S., Graves, M.C., McCluskey, L.F., Barohn, R.J., Tandan, R.; and Western ALS Study Group 2007. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 6:1045‐1053.
  Gurney, M.E., Pu, H., Chiu, A.Y., Dal Canto, M.C., Polchow, C.Y., Alexander, D.D., Caliendo, J., Hentati, A., Kwon, Y.W., Deng, H.X. et al. 1994. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264:1772‐1775.
  Haidet‐Phillips, A.M., Gross, S.K., Williams, T., Tuteja, A., Sherman, A., Ko, M., Jeong, Y.H., Wong, P.C., and Maragakis, N.J. 2013. Altered astrocytic expression of TDP‐43 does not influence motor neuron survival. Exp. Neurol. 250:250‐259.
  Hatzipetros, T., Bogdanik, L.P., Tassinari, V.R., Kidd, J.D., Moreno, A.J., Davis, C., Osborne, M., Austin, A., Vieira, F.G., Lutz, C., and Perrin, S. 2013. C57BL/6J congenic Prp‐TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS. Brain Res. 1584:59‐72.
  Herdewyn, S., Cirillo, C., Van Den Bosch, L., Robberecht, W., Vanden Berghe, P., and Van Damme, P. 2014. Prevention of intestinal obstruction reveals progressive neurodegeneration in mutant TDP‐43 (A315T) mice. Mol. Neurodegen. 9:24.
  Howland, D.S., Liu, J., She, Y., Goad, B., Maragakis, N.J., Kim, B., Erickson, J., Kulik, J., DeVito, L., Psaltis, G., DeGennaro, L.J., Cleveland, D.W., and Rothstein, J.D. 2002. 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. 99:1604‐1609.
  Huang, C., Tong, J., Bi, F., Zhou, H., and Xia, X.G. 2012. Mutant TDP‐43 in motor neurons promotes the onset and progression of ALS in rats. J. Clin. Invest. 122:107‐118.
  Igaz, L.M., Kwong, L.K., Lee, E.B., Chen‐Plotkin, A., Swanson, E., Unger, T., Malunda, J., Xu, Y., Winton, M.J., Trojanowski, J.Q., and Lee, V.M. 2011. Dysregulation of the ALS‐associated gene TDP‐43 leads to neuronal death and degeneration in mice. J. Clin. Invest.121:726‐738.
  Iguchi, Y., Katsuno, M., Niwa, J., Takagi, S., Ishigaki, S., Ikenaka, K., Kawai, K., Watanabe, H., Yamanaka, K., Takahashi, R., Misawa, H., Sasaki, S., Tanaka, F., and Sobue, G. 2013. Loss of TDP‐43 causes age‐dependent progressive motor neuron degeneration. Brain 136:1371‐1382.
  Jaarsma, D., Teuling, E., Haasdijk, E.D., De Zeeuw, C.I., and Hoogenraad, C.C. 2008. Neuron‐specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J. Neurosci. 28:2075‐2088.
  Janssens, J., Wils, H., Kleinberger, G., Joris, G., Cuijt, I., Ceuterick‐de Groote, C., Van Broeckhoven, C., and Kumar‐Singh, S. 2013. Overexpression of ALS‐associated p.M337V human TDP‐43 in mice worsens disease features compared to wild‐type human TDP‐43 mice. Mol. Neurobiol. 48:22‐35.
  Johnson, J.O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V.M., Trojanowski, J.Q., Gibbs, J.R., Brunetti, M., Gronka, S., Wuu, J., Ding, J., McCluskey, L., Martinez‐Lage, M., Falcone, D., Hernandez, D.G., Arepalli, S., Chong, S., Schymick, J.C., Rothstein, J., Landi, F., Wang, Y.D., Calvo, A., Mora, G., Sabatelli, M., Monsurrò, M.R., Battistini, S., Salvi, F., Spataro, R., Sola, P., Borghero, G.; ITALSGEN Consortium, Galassi, G., Scholz, S.W., Taylor, J.P., Restagno, G., Chiò, A., and Traynor, B.J. 2010. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857‐864.
  Johnson, J.O. Pioro, E.P., Boehringer, A., Chia, R., Feit, H., Renton, A.E., Pliner, H.A., Abramzon, Y., Marangi, G., Winborn, B.J., Gibbs, J.R., Nalls, M.A., Morgan, S., Shoai, M., Hardy, J., Pittman, A., Orrell, R.W., Malaspina, A., Sidle, K.C., Fratta, P., Harms, M.B., Baloh, R.H., Pestronk, A., Weihl, C.C., Rogaeva, E., Zinman, L., Drory, V.E., Borghero, G., Mora, G., Calvo, A., Rothstein, J.D.; ITALSGEN Consortium, Drepper, C., Sendtner, M., Singleton, A.B., Taylor, J.P., Cookson, M.R., Restagno, G., Sabatelli, M., Bowser, R., Chiò, A., and Traynor, B.J. 2014. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat. Neurosci. 17:664‐666.
  Joyce, P.I., Fratta, P., Fisher, E.M., and Acevedo‐Arozena, A. 2011. SOD1 and TDP‐43 animal models of amyotrophic lateral sclerosis: recent advances in understanding disease toward the development of clinical treatments. Mamm. Genome 22:420‐448.
  Kalra, S., Genge, A., and Arnold, D.L. 2003. A prospective, randomized, placebo‐controlled evaluation of corticoneuronal response to intrathecal BDNF therapy in ALS using magnetic resonance spectroscopy: Feasibility and results. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 4:22‐26.
  Kang, S.H., Li, Y., Fukaya, M., Lorenzini, I., Cleveland, D.W., Ostrow, L.W., Rothstein, J.D., and Bergles, D.E. 2013. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat. Neurosci. 16:571‐579.
  Kondo, T., Reaume, A.G., Huang, T.T., Carlson, E., Murakami, K., Chen, S.F., Hoffman, E.K., Scott, R.W., Epstein, C.J., and Chan, P.H. 1997. Reduction of CuZn‐superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J. Neurosci. 17:4180‐4189.
  Kraemer, B.C., Schuck, T., Wheeler, J.M., Robinson, L.C., Trojanowski, J.Q., Lee, V.M., and Schellenberg, G.D. 2010. Loss of murine TDP‐43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol. 119:409‐419.
  Kriz, J., Nguyen, M.D., and Julien, J.P. 2002. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 10:268‐278.
  Kwiatkowski, T.J. Jr., Bosco, D.A., Leclerc, A.L., Tamrazian, E., Vanderburg, C.R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E.J., Munsat, T., Valdmanis, P., Rouleau, G.A., Hosler, B.A., Cortelli, P., de Jong, P.J., Yoshinaga, Y., Haines, J.L., Pericak‐Vance, M.A., Yan, J., Ticozzi, N., Siddique, T., McKenna‐Yasek, D., Sapp, P.C., Horvitz, H.R., Landers, J.E., and Brown, R.H. Jr. 2009. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205‐1208.
  Lagier‐Tourenne, C., Polymenidou, M., Hutt, K.R., Vu, A.Q., Baughn, M., Huelga, S.C., Clutario, K.M., Ling, S.C., Liang, T.Y., Mazur, C., Wancewicz, E., Kim, A.S., Watt, A., Freier, S., Hicks, G.G., Donohue, J.P., Shiue, L., Bennett, C.F., Ravits, J., Cleveland, D.W., and Yeo, G.W. 2012. Divergent roles of ALS‐linked proteins FUS/TLS and TDP‐43 intersect in processing long pre‐mRNAs. Nat. Neurosci. 15:1488‐1497.
  Leblond, C.S., Kaneb, H.M., Dion, P.A., and Rouleau, G.A. 2014. Dissection of genetic factors associated with amyotrophic lateral sclerosis. Exp. Neurol. 262:91‐101.
  Lee, E.B., Lee, V.M., and Trojanowski, J.Q. 2012. Gains or losses: Molecular mechanisms of TDP43‐mediated neurodegeneration. Nat. Rev. Neurosci. 13:38‐50.
  Lee, Y., Morrison, B.M., Li, Y., Lengacher, S., Farah, M.H., Hoffman, P.N., Liu, Y., Tsingalia, A., Jin, L., Zhang, P.W., Pellerin, L., Magistretti, P.J., and Rothstein, J.D. 2012. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487:443‐448.
  Lino, M.M., Schneider, C., and Caroni, P. 2002. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J. Neurosci. 22:4825‐4832.
  Maruyama, H., Morino, H., Ito, H., Izumi, Y., Kato, H., Watanabe, Y., Kinoshita, Y., Kamada, M., Nodera, H., Suzuki, H., Komure, O., Matsuura, S., Kobatake, K., Morimoto, N., Abe, K., Suzuki, N., Aoki, M., Kawata, A., Hirai, T., Kato, T., Ogasawara, K., Hirano, A., Takumi, T., Kusaka, H., Hagiwara, K., Kaji, R., and Kawakami, H. 2010. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223‐226.
  Mayford, M., Bach, M.E., Huang, Y.Y., Wang, L., Hawkins, R.D., and Kandel, E.R. 1996. Control of memory formation through regulated expression of a CaMKII transgene. Science 274:1678‐1683.
  Miller, R.G., Petajan, J.H., Bryan, W.W., Armon, C., Barohn, R.J., Goodpasture, J.C., Hoagland, R.J., Parry, G.J., Ross, M.A., and Stromatt, S.C. 1996. A placebo‐controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann. Neurol. 39:256‐260.
  Nagy, D., Kato, T., and Kushner, P.D. 1994. Reactive astrocytes are widespread in the cortical gray matter of amyotrophic lateral sclerosis. J. Neurosci. Res. 38:336‐347.
  Nalbandian, A., Llewellyn, K.J., Badadani, M., Yin, H.Z., Nguyen, C., Katheria, V., Watts, G., Mukherjee, J., Vesa, J., Caiozzo, V., Mozaffar, T., Weiss, J.H., and Kimonis, V.E. 2013. A progressive translational mouse model of human valosin‐containing protein disease: the VCP(R155H/+) mouse. Muscle Nerve 47:260‐270.
  Neumann, M., Sampathu, D.M., Kwong, L.K., Truax, A.C., Micsenyi, M.C., Chou, T.T., Bruce, J., Schuck, T., Grossman, M., Clark, C.M., McCluskey, L.F., Miller, B.L., Masliah, E., Mackenzie, I.R., Feldman, H., Feiden, W., Kretzschmar, H.A., Trojanowski, J.Q., and Lee, V.M. 2006. Ubiquitinated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130‐133.
  Osborne, R.A., Sekhon, R., Johnston, W., and Kalra, S. 2014. Screening for frontal lobe and general cognitive impairment in patients with amyotrophic lateral sclerosis. J. Neurol. Sci. 336:191‐196.
  Ozdinler, P.H., Benn, S., Yamamoto, T.H., Guzel, M., Brown, R.H. Jr., and Macklis, J.D. (2011). Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G(9)(3)A transgenic ALS mice. J. Neurosci. 31:4166‐4177.
  Perrin, S. 2014. Preclinical research: Make mouse studies work. Nature 507:423‐425.
  Philips, T. and Robberecht, W. 2011. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 10:253‐263.
  Philips, T. and Rothstein, J.D. 2014. Glial cells in amyotrophic lateral sclerosis. Exp. Neurol. 262B:111‐120.
  Philips, T., Bento‐Abreu, A., Nonneman, A., Haeck, W., Staats, K., Geelen, V., Hersmus, N., Kusters, B., Van Den Bosch, L., Van Damme, P., Richardson, W.D., and Robberecht, W. 2013. Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain 136:471‐482.
  Pramatarova, A., Laganiere, J., Roussel, J., Brisebois, K., and Rouleau, G.A. 2001. Neuron‐specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J. Neurosci. 21:3369‐3374.
  Pronto‐Laborinho, A.C., Pinto, S., and de Carvalho, M. 2014. Roles of vascular endothelial growth factor in amyotrophic lateral sclerosis. BioMed Res. Int. 2014:947513.
  Qiu, H., Lee, S., Shang, Y., Wang, W.Y., Au, K.F., Kamiya, S., Barmada, S.J., Finkbeiner, S., Lui, H., Carlton, C.E., Tang, A.A., Oldham, M.C., Wang, H., Shorter, J., Filiano, A.J., Roberson, E.D., Tourtellotte, W.G., Chen, B., Tsai, L.H., and Huang, E.J. 2014. ALS‐associated mutation FUS‐R521C causes DNA damage and RNA splicing defects. J. Clin. Invest. 124:981‐999.
  Renton, A.E., Majounie, E., Waite, A., Simón‐Sánchez, J., Rollinson, S., Gibbs, J.R., Schymick, J.C., Laaksovirta, H., van Swieten, J.C., Myllykangas, L., Kalimo, H., Paetau, A., Abramzon, Y., Remes, A.M., Kaganovich, A., Scholz, S.W., Duckworth, J., Ding, J., Harmer, D.W., Hernandez, D.G., Johnson, J.O., Mok, K., Ryten, M., Trabzuni, D., Guerreiro, R.J., Orrell, R.W., Neal, J., Murray, A., Pearson, J., Jansen, I.E., Sondervan, D., Seelaar, H., Blake, D., Young, K., Halliwell, N., Callister, J.B., Toulson, G., Richardson, A., Gerhard, A., Snowden, J., Mann, D., Neary, D., Nalls, M.A., Peuralinna, T., Jansson, L., Isoviita, V.M., Kaivorinne, A.L., Hölttä‐Vuori, M., Ikonen, E., Sulkava, R., Benatar, M., Wuu, J., Chiò, A., Restagno, G., Borghero, G., Sabatelli, M.; ITALSGEN Consortium, Heckerman, D., Rogaeva, E., Zinman, L., Rothstein, J.D., Sendtner, M., Drepper, C., Eichler, E.E., Alkan, C., Abdullaev, Z., Pack, S.D., Dutra, A., Pak, E., Hardy, J., Singleton, A., Williams, N.M., Heutink, P., Pickering‐Brown, S., Morris, H.R., Tienari, P.J., and Traynor, B.J. 2011. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21‐linked ALS‐FTD. Neuron 72:257‐268.
  Renton, A.E., Chio, A., and Traynor, B.J. 2014. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 17:17‐23.
  Ringholz, G.M., Appel, S.H., Bradshaw, M., Cooke, N.A., Mosnik, D.M., and Schulz, P.E. 2005. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65:586‐590.
  Ripps, M.E., Huntley, G.W., Hof, P.R., Morrison, J.H., and Gordon, J.W. 1995. Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. U.S.A. 92:689‐693.
  Rosen, D.R. 1993. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364:362.
  Rothstein, J.D., Martin, L.J., and Kuncl, R.W. 1992. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N. Engl. J. Med. 326:1464‐1468.
  Rothstein, J.D., Patel, S., Regan, M.R., Haenggeli, C., Huang, Y.H., Bergles, D.E., Jin, L., Dykes Hoberg, M., Vidensky, S., Chung, D.S., Toan, S.V., Bruijn, L.I., Su, Z.Z., Gupta, P., and Fisher, P.B. 2005. Beta‐lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73‐77.
  Rutherford, N.J., Zhang, Y.J., Baker, M., Gass, J.M., Finch, N.A., Xu, Y.F., Stewart, H., Kelley, B.J., Kuntz, K., Crook, R.J., Sreedharan, J., Vance, C., Sorenson, E., Lippa, C., Bigio, E.H., Geschwind, D.H., Knopman, D.S., Mitsumoto, H., Petersen, R.C., Cashman, N.R., Hutton, M., Shaw, C.E., Boylan, K.B., Boeve, B., Graff‐Radford, N.R., Wszolek, Z.K., Caselli, R.J., Dickson, D.W., Mackenzie, I.R., Petrucelli, L., and Rademakers, R. 2008. Novel mutations in TARDBP (TDP‐43) in patients with familial amyotrophic lateral sclerosis. PLoS Genetics 4:e1000193.
  Saxena, S., Cabuy, E., and Caroni, P. 2009. A role for motoneuron subtype‐selective ER stress in disease manifestations of FALS mice. Nat. Neurosci. 12:627‐636.
  Seilhean, D., Cazeneuve, C., Thuries, V., Russaouen, O., Millecamps, S., Salachas, F., Meininger, V., Leguern, E., and Duyckaerts, C. 2009. Accumulation of TDP‐43 and alpha‐actin in an amyotrophic lateral sclerosis patient with the K17I ANG mutation. Acta Neuropathol. 118:561‐573.
  Sephton, C.F., Tang, A.A., Kulkarni, A., West, J., Brooks, M., Stubblefield, J.J., Liu, Y., Zhang, M.Q., Green, C.B., Huber, K.M., Huang, E.J., Herz, J., and Yu, G. 2014. Activity-dependent FUS dysregulation disrupts synaptic homeostasis. Proc. Natl. Acad. Sci. U.S.A. 111:E4769‐E4778.
  Serio, A., Bilican, B., Barmada, S.J., Ando, D.M., Zhao, C., Siller, R., Burr, K., Haghi, G., Story, D., Nishimura, A.L., Carrasco, M.A., Phatnani, H.P., Shum, C., Wilmut, I., Maniatis, T., Shaw, C.E., Finkbeiner, S., and Chandran, S. 2013. Astrocyte pathology and the absence of non‐cell autonomy in an induced pluripotent stem cell model of TDP‐43 proteinopathy. Proc. Natl. Acad. Sci. U.S.A. 110:4697‐4702.
  Shan, X., Chiang, P.M., Price, D.L., and Wong, P.C. 2010. Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP‐43 transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 107:16325‐16330.
  Shefner, J.M., Reaume, A.G., Flood, D.G., Scott, R.W., Kowall, N.W., Ferrante, R.J., Siwek, D.F., Upton‐Rice, M., and Brown, R.H. Jr. 1999. Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy. Neurology 53:1239‐1246.
  Sorenson, E.J., Windbank, A.J., Mandrekar, J.N., Bamlet, W.R., Appel, S.H., Armon, C., Barkhaus, P.E., Bosch, P., Boylan, K., David, W.S., Feldman, E., Glass, J., Gutmann, L., Katz, J., King, W., Luciano, C.A., McCluskey, L.F., Nash, S., Newman, D.S., Pascuzzi, R.M., Pioro, E., Sams, L.J., Scelsa, S., Simpson, E.P., Subramony, S.H., Tiryaki, E., and Thornton, C.A. 2008. Subcutaneous IGF‐1 is not beneficial in 2‐year ALS trial. Neurology 71:1770‐1775.
  Sorrells, A.D., Corcoran‐Gomez, K., Eckert, K.A., Fahey, A.G., Hoots, B.L., Charleston, L.B., Charleston, J.S., Roberts, C.R., and Markowitz, H. 2009. Effects of environmental enrichment on the amyotrophic lateral sclerosis mouse model. Lab. Animals 43:182‐190.
  Sreedharan, J., Blair, I.P., Tripathi, V.B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J.C., Williams, K.L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J.D., Leigh, P.N., Al‐Chalabi, A., Miller, C.C., Nicholson, G., and Shaw, C.E. 2008. TDP‐43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668‐1672.
  Stallings, N.R., Puttaparthi, K., Luther, C.M., Burns, D.K., and Elliott, J.L. 2010. Progressive motor weakness in transgenic mice expressing human TDP‐43. Neurobiol. Dis. 40:404‐414.
  Stam, N.C., Nithianantharajah, J., Howard, M.L., Atkin, J.D., Cheema, S.S., and Hannan, A.J. 2008. Sex‐specific behavioural effects of environmental enrichment in a transgenic mouse model of amyotrophic lateral sclerosis. Eur. J. Neurosci. 28:717‐723.
  Sun, Z., Diaz, Z., Fang, X., Hart, M.P., Chesi, A., Shorter, J., and Gitler, A.D. 2011. Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biology 9:e1000614.
  Swarup, V., Phaneuf, D., Bareil, C., Robertson, J., Rouleau, G.A., Kriz, J., and Julien, J.P. 2011a. Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP‐43 genomic fragments. Brain 134:2610‐2626.
  Swarup, V., Phaneuf, D., Dupre, N., Petri, S., Strong, M., Kriz, J., and Julien, J.P. 2011b. Deregulation of TDP‐43 in amyotrophic lateral sclerosis triggers nuclear factor kB‐mediated pathogenic pathways. J. Exp. Med. 208:2429‐2447.
  Taneja, K.L., McCurrach, M., Schalling, M., Housman, D., and Singer, R.H. 1995. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J. Cell Biol. 128:995‐1002.
  Tong, J., Huang, C., Bi, F., Wu, Q., Huang, B., Liu, X., Li, F., Zhou, H., and Xia, X.G. 2013. Expression of ALS‐linked TDP‐43 mutant in astrocytes causes non‐cell‐autonomous motor neuron death in rats. EMBO J. 32:1917‐1926.
  Tsai, K.J., Yang, C.H., Fang, Y.H., Cho, K.H., Chien, W.L., Wang, W.T., Wu, T.W., Lin, C.P., Fu, W.M., and Shen, C.K. 2010. Elevated expression of TDP‐43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD‐U. J. Exp. Med. 207:1661‐1673.
  Tsao, W., Jeong, Y.H., Lin, S., Ling, J., Price, D.L., Chiang, P.M., and Wong, P.C. 2012. Rodent models of TDP‐43: Recent advances. Brain Res. 1462:26‐39.
  Turner, B.J., Ackerley, S., Davies, K.E., and Talbot, K. 2010. Dismutase‐competent SOD1 mutant accumulation in myelinating Schwann cells is not detrimental to normal or transgenic ALS model mice. Hum. Mol. Genet. 19:815‐824.
  van Blitterswijk, M., van Es, M.A., Hennekam, E.A., Dooijes, D., van Rheenen, W., Medic, J., Bourque, P.R., Schelhaas, H.J., van der Kooi, A.J., de Visser, M., de Bakker, P.I., Veldink, J.H., and van den Berg, L.H. 2012. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum. Mol. Genet. 21:3776‐3784.
  Van Damme, P., Braeken, D., Callewaert, G., Robberecht, W., and Van Den Bosch, L. 2005. GluR2 deficiency accelerates motor neuron degeneration in a mouse model of amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 64:605‐612.
  Van Den Bosch, L., Tilkin, P., Lemmens, G., and Robberecht, W. 2002. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport 13:1067‐1070.
  Van Hoecke, A., Schoonaert, L., Lemmens, R., Timmers, M., Staats, K.A., Laird, A.S., Peeters, E., Philips, T., Goris, A., Dubois, B., Andersen, P.M., Al-Chalabi, A., Thijs, V., Turnley, A.M., van Vught, P.W., Veldink, J.H., Hardiman, O., Van Den Bosch, L., Gonzalez-Perez, P., Van Damme, P., Brown R.H., Jr., van den Berg, L.H., and Robberecht, W. 2012. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat. Med. 18:1418‐1422.
  Vance, C., Rogelj, B., Hortobágyi, T., De Vos, K.J., Nishimura, A.L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K.L., Tripathi, V., Al‐Saraj, S., Al‐Chalabi, A., Leigh, P.N., Blair, I.P., Nicholson, G., de Belleroche, J., Gallo, J.M., Miller, C.C., and Shaw, C.E. 2009. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208‐1211.
  Watts, G.D., Wymer, J., Kovach, M.J., Mehta, S.G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M.P., and Kimonis, V.E. 2004. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin‐containing protein. Nat. Genetics 36:377‐381.
  Wegorzewska, I., Bell, S., Cairns, N.J., Miller, T.M., and Baloh, R.H. 2009. TDP‐43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc. Natl. Acad. Sci. U.S.A. 106:18809‐18814.
  Weihl, C.C., Miller, S.E., Hanson, P.I., and Pestronk, A. 2007. Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice. Hum. Mol. Genet. 16:919‐928.
  Wils, H., Kleinberger, G., Janssens, J., Pereson, S., Joris, G., Cuijt, I., Smits, V., Ceuterick‐de Groote, C., Van Broeckhoven, C., and Kumar‐Singh, S. 2010. TDP‐43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc. Natl. Acad. Sci. U.S.A. 107:3858‐3863.
  Wong, P.C., Pardo, C.A., Borchelt, D.R., Lee, M.K., Copeland, N.G., Jenkins, N.A., Sisodia, S.S., Cleveland, D.W., and Price, D.L. 1995. An adverse property of a familial ALS‐linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:1105‐1116.
  Wu, L.S., Cheng, W.C., and Shen, C.K. 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. 287:27335‐27344.
  Xu, Y.F., Gendron, T.F., Zhang, Y.J., Lin, W.L., D'Alton, S., Sheng, H., Casey, M.C., Tong, J., Knight, J., Yu, X., Rademakers, R., Boylan, K., Hutton, M., McGowan, E., Dickson, D.W., Lewis, J., and Petrucelli, L. 2010. Wild‐type human TDP‐43 expression causes TDP‐43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J. Neurosci. 30:10851‐10859.
  Xu, Y.F., Zhang, Y.J., Lin, W.L., Cao, X., Stetler, C., Dickson, D.W., Lewis, J., and Petrucelli, L. 2011. Expression of mutant TDP‐43 induces neuronal dysfunction in transgenic mice. Mol. Neurodegen. 6:73.
  Xu, Y.F., Prudencio, M., Hubbard, J.M., Tong, J., Whitelaw, E.C., Jansen‐West, K., Stetler, C., Cao, X., Song, J., and Zhang, Y.J. 2013. The pathological phenotypes of human TDP‐43 transgenic mouse models are independent of downregulation of mouse Tdp‐43. PLoS One 8:e69864.
  Yamanaka, K., Boillee, S., Roberts, E.A., Garcia, M.L., McAlonis‐Downes, M., Mikse, O.R., Cleveland, D.W., and Goldstein, L.S. 2008. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl. Acad. Sci. U.S.A. 105:7594‐7599.
  Yang, C., Wang, H., Qiao, T., Yang, B., Aliaga, L., Qiu, L., Tan, W., Salameh, J., McKenna‐Yasek, D.M., Smith, T., Peng, L., Moore, M.J., Brown, R.H. Jr., Cai, H., and Xu, Z. 2014. Partial loss of TDP‐43 function causes phenotypes of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. U.S.A. 111:E1121‐1129.
  Zhou, H., Huang, C., Chen, H., Wang, D., Landel, C.P., Xia, P.Y., Bowser, R., Liu, Y.J., and Xia, X.G. 2010. Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genetics 6:e1000887.
  Zhu, S., Stavrovskaya, I.G., Drozda, M., Kim, B.Y., Ona, V., Li, M., Sarang, S., Liu, A.S., Hartley, D.M., Wu, D.C., Gullans, S., Ferrante, R.J., Przedborski, S., Kristal, B.S., and Friedlander, R.M. 2002. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417:74‐78.
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