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Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions

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Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease characterized by degeneration of motor neurons, resulting in paralysis and death. A pathological hallmark of the degenerating motor neurons in most ALS patients is the presence of cytoplasmic inclusions containing the protein TDP-43. The morphology and type of TDP-43 pathological inclusions is variable and can range from large round Lewy body-like inclusions to filamentous skein-like inclusions. The clinical significance of this variable pathology is unclear. Intermediate-length polyglutamine (polyQ) expansions in ataxin 2 were recently identified as a genetic risk factor for ALS. Here we have analyzed TDP-43 pathology in a series of ALS cases with or without ataxin 2 intermediate-length polyQ expansions. The motor neurons of ALS cases harboring ataxin 2 polyQ expansions (n = 6) contained primarily skein-like or filamentous TDP-43 pathology and only rarely, if ever, contained large round inclusions, whereas the ALS cases without ataxin 2 polyQ expansions (n = 13) contained abundant large round and skein-like TDP-43 pathology. The paucity of large round TDP-43 inclusions in ALS cases with ataxin 2 polyQ expansions suggests a distinct pathological subtype of ALS and highlights the possibility for distinct pathogenic mechanisms.

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References

  1. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, Rogelj B, Al-Chalabi A, Hortobagyi T, Shaw CE (2011) p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol 122:691–702

    Article  PubMed  CAS  Google Scholar 

  2. Blair IP, Williams KL, Warraich ST, Durnall JC, Thoeng AD, Manavis J, Blumbergs PC, Vucic S, Kiernan MC, Nicholson GA (2010) FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J Neurol Neurosurg Psychiatry 81:20881–20890

    Article  Google Scholar 

  3. Boeve BF, Boylan KB, Graff-Radford NR, Dejesus-Hernandez M, Knopman DS, Pedraza O, Vemuri P, Jones D, Lowe V, Murray ME, Dickson DW, Josephs KA, Rush BK, Machulda MM, Fields JA, Ferman TJ, Baker M, Rutherford NJ, Adamson J, Wszolek ZK, Adeli A, Savica R, Boot B, Kuntz KM, Gavrilova R, Reeves A, Whitwell J, Kantarci K, Jack CR Jr, Parisi JE, Lucas JA, Petersen RC, Rademakers R (2012) Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135:765–783

    Article  PubMed  Google Scholar 

  4. Brettschneider J, Libon DJ, Toledo JB, Xie SX, McCluskey L, Elman L, Geser F, Lee VM, Grossman M, Trojanowski JQ (2012) Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis. Acta Neuropathol 123:395–407

    Article  PubMed  CAS  Google Scholar 

  5. Brettschneider J, Van Deerlin VM, Robinson JL, Kwong L, Lee EB, Ali YO, Safren N, Monteiro MJ, Toledo JB, Elman L, McCluskey L, Irwin DJ, Grossman M, Molina-Porcel L, Lee VM, Trojanowski JQ (2012) Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol. doi:10.1007/s00401-012-0970-z

    Google Scholar 

  6. Brooks BR, Miller RG, Swash M, Munsat TL (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299

    Article  PubMed  CAS  Google Scholar 

  7. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 169:13–21

    Article  PubMed  CAS  Google Scholar 

  8. Chen Y, Huang R, Yang Y, Chen K, Song W, Pan P, Li J, Shang HF (2011) Ataxin-2 intermediate-length polyglutamine: a possible risk factor for Chinese patients with amyotrophic lateral sclerosis. Neurobiol Aging 32:1925.e1–5

    Google Scholar 

  9. Chen-Plotkin AS, Martinez-Lage M, Sleiman PM, Hu W, Greene R, Wood EM, Bing S, Grossman M, Schellenberg GD, Hatanpaa KJ, Weiner MF, White CL 3rd, Brooks WS, Halliday GM, Kril JJ, Gearing M, Beach TG, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Pickering-Brown SM, Snowden J, van Swieten JC, Heutink P, Seelaar H, Murrell JR, Ghetti B, Spina S, Grafman J, Kaye JA, Woltjer RL, Mesulam M, Bigio E, Llado A, Miller BL, Alzualde A, Moreno F, Rohrer JD, Mackenzie IR, Feldman HH, Hamilton RL, Cruts M, Engelborghs S, De Deyn PP, Van Broeckhoven C, Bird TD, Cairns NJ, Goate A, Frosch MP, Riederer PF, Bogdanovic N, Lee VM, Trojanowski JQ, Van Deerlin VM (2011) Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. Arch Neurol 68:488–497

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S, Martindale J, Hartley J, Walsh T, Gelsthorpe C, Baxter L, Forster G, Fox M, Bury J, Mok K, McDermott CJ, Traynor BJ, Kirby J, Wharton SB, Ince PG, Hardy J, Shaw PJ (2012) Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain 135:751–764

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  13. Daoud H, Belzil V, Martins S, Sabbagh M, Provencher P, Lacomblez L, Meininger V, Camu W, Dupre N, Dion PA, Rouleau GA (2011) Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis. Arch Neurol 68:739–742

    Article  PubMed  Google Scholar 

  14. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rub U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075

    Article  PubMed  CAS  Google Scholar 

  15. Fischbeck KH, Pulst SM (2011) Amyotrophic lateral sclerosis and spinocerebellar ataxia 2. Neurology 76:2050–2051

    Article  PubMed  Google Scholar 

  16. Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, Van Deerlin V, Lee VM, Miller BL, Trojanowski JQ, Grossman M (2006) Frontotemporal dementia: clinicopathological correlations. Ann Neurol 59:952–962

    Article  PubMed  Google Scholar 

  17. Forman MS, Trojanowski JQ, Lee VM (2004) Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 10:1055–1063

    Article  PubMed  CAS  Google Scholar 

  18. Geser F, Martinez-Lage M, Robinson J, Uryu K, Neumann M, Brandmeir NJ, Xie SX, Kwong LK, Elman L, McCluskey L, Clark CM, Malunda J, Miller BL, Zimmerman EA, Qian J, Van Deerlin V, Grossman M, Lee VM, Trojanowski JQ (2009) Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol 66:180–189

    Article  PubMed  Google Scholar 

  19. Geser F, Robinson JL, Malunda JA, Xie SX, Clark CM, Kwong LK, Moberg PJ, Moore EM, Van Deerlin VM, Lee VM, Arnold SE, Trojanowski JQ (2010) Pathological 43-kDa transactivation response DNA-binding protein in older adults with and without severe mental illness. Arch Neurol 67:1238–1250

    Article  PubMed  Google Scholar 

  20. Geser F, Stein B, Partain M, Elman LB, McCluskey LF, Xie SX, Van Deerlin VM, Kwong LK, Lee VM, Trojanowski JQ (2011) Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy. Acta Neuropathol 121:509–517

    Article  PubMed  Google Scholar 

  21. Gispert S, Kurz A, Waibel S, Bauer P, Liepelt I, Geisen C, Gitler AD, Becker T, Weber M, Berg D, Andersen PM, Kruger R, Riess O, Ludolph AC, Auburger G (2012) The modulation of amyotrophic lateral sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect. Neurobiol Dis 45:356–361

    Article  PubMed  CAS  Google Scholar 

  22. Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL 3rd, Bigio EH, Caselli R, Baker M, Al-Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538

    Article  PubMed  CAS  Google Scholar 

  23. Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle F, Morita M, Nakano I, Oda T, Tsuchiya K, Akiyama H (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64:60–70

    Article  PubMed  CAS  Google Scholar 

  24. Hsiung GY, Dejesus-Hernandez M, Feldman HH, Sengdy P, Bouchard-Kerr P, Dwosh E, Butler R, Leung B, Fok A, Rutherford NJ, Baker M, Rademakers R, Mackenzie IR (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135:709–722

    Article  PubMed  Google Scholar 

  25. Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N, Durr A, Didierjean O, Stevanin G, Agid Y, Brice A (1996) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 14:285–291

    Article  PubMed  CAS  Google Scholar 

  26. Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD (2009) TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem 284:20329–20339

    Article  PubMed  CAS  Google Scholar 

  27. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  29. Lagier-Tourenne C, Cleveland DW (2010) Neurodegeneration: an expansion in ALS genetics. Nature 466:1052–1053

    Article  PubMed  CAS  Google Scholar 

  30. Lee EB, Lee VM, Trojanowski JQ (2012) Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13:38–50

    CAS  Google Scholar 

  31. Lee T, Li YR, Ingre C, Weber M, Grehl T, Gredal O, de Carvalho M, Meyer T, Tysnes OB, Auburger G, Gispert S, Bonini NM, Andersen PM, Gitler AD (2011) Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum Mol Genet 20:1697–1700

    Article  PubMed  CAS  Google Scholar 

  32. Lorenzetti D, Bohlega S, Zoghbi HY (1997) The expansion of the CAG repeat in ataxin-2 is a frequent cause of autosomal dominant spinocerebellar ataxia. Neurology 49:1009–1013

    Article  PubMed  CAS  Google Scholar 

  33. Mackenzie IR, Ansorge O, Strong M, Bilbao J, Zinman L, Ang LC, Baker M, Stewart H, Eisen A, Rademakers R, Neumann M (2011) Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neuropathol 122:87–98

    Article  PubMed  Google Scholar 

  34. Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H, Eisen A, McClusky L, Kretzschmar HA, Monoranu CM, Highley JR, Kirby J, Siddique T, Shaw PJ, Lee VM, Trojanowski JQ (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434

    Article  PubMed  CAS  Google Scholar 

  35. Mackenzie IR, Munoz DG, Kusaka H, Yokota O, Ishihara K, Roeber S, Kretzschmar HA, Cairns NJ, Neumann M (2010) Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 121:207–218

    Article  PubMed  Google Scholar 

  36. Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113

    Article  PubMed  Google Scholar 

  37. Mizuno Y, Fujita Y, Takatama M, Okamoto K (2012) Comparison of phosphorylated TDP-43-positive inclusions in oculomotor neurons in patients with non-ALS and ALS disorders. J Neurol Sci 315:20–25

    Article  PubMed  CAS  Google Scholar 

  38. Mori F, Tanji K, Zhang HX, Nishihira Y, Tan CF, Takahashi H, Wakabayashi K (2008) Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia. Acta Neuropathol 116:193–203

    Article  PubMed  CAS  Google Scholar 

  39. Murray ME, DeJesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR, Wszolek ZK, Ferman TJ, Josephs KA, Boylan KB, Rademakers R, Dickson DW (2011) Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 122:673–690

    Article  PubMed  CAS  Google Scholar 

  40. Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, Forman MS, Troost D, Kretzschmar HA, Trojanowski JQ, Lee VM (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137–149

    Article  PubMed  CAS  Google Scholar 

  41. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  PubMed  CAS  Google Scholar 

  42. Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa C, Sahba S (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 14:269–276

    Article  PubMed  CAS  Google Scholar 

  43. Ross OA, Rutherford NJ, Baker M, Soto-Ortolaza AI, Carrasquillo MM, DeJesus-Hernandez M, Adamson J, Li M, Volkening K, Finger E, Seeley WW, Hatanpaa KJ, Lomen-Hoerth C, Kertesz A, Bigio EH, Lippa C, Woodruff BK, Knopman DS, White CL 3rd, Van Gerpen JA, Meschia JF, Mackenzie IR, Boylan K, Boeve BF, Miller BL, Strong MJ, Uitti RJ, Younkin SG, Graff-Radford NR, Petersen RC, Wszolek ZK, Dickson DW, Rademakers R (2011) Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet 20:3207–3212

    Article  PubMed  CAS  Google Scholar 

  44. Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, Wakisaka A, Tashiro K, Ishida Y, Ikeuchi T, Koide R, Saito M, Sato A, Tanaka T, Hanyu S, Takiyama Y, Nishizawa M, Shimizu N, Nomura Y, Segawa M, Iwabuchi K, Eguchi I, Tanaka H, Takahashi H, Tsuji S (1996) Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 14:277–284

    Article  PubMed  CAS  Google Scholar 

  45. See TM, LaMarre AK, Lee SE, Miller BL (2010) Genetic causes of frontotemporal degeneration. J Geriatr Psychiatry Neurol 23:260–268

    Article  PubMed  Google Scholar 

  46. Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AM, Jones M, Gerhard A, Davidson YS, Robinson A, Gibbons L, Hu Q, Duplessis D, Neary D, Mann DM, Pickering-Brown SM (2012) Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135:693–708

    Article  PubMed  Google Scholar 

  47. Soraru G, Clementi M, Forzan M, Orsetti V, D’Ascenzo C, Querin G, Palmieri A, Ermani M, Angelini C, Pegoraro E (2011) ALS risk but not phenotype is affected by ataxin-2 intermediate length polyglutamine expansion. Neurology 76:2030–2031

    Article  PubMed  CAS  Google Scholar 

  48. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672

    Article  PubMed  CAS  Google Scholar 

  49. Stewart H, Rutherford NJ, Briemberg H, Krieger C, Cashman N, Fabros M, Baker M, Fok A, Dejesus-Hernandez M, Eisen A, Rademakers R, Mackenzie IR (2012) Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol 123:409–417

    Article  PubMed  CAS  Google Scholar 

  50. Tan CF, Eguchi H, Tagawa A, Onodera O, Iwasaki T, Tsujino A, Nishizawa M, Kakita A, Takahashi H (2007) TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol 113:535–542

    Article  PubMed  CAS  Google Scholar 

  51. Thorpe JR, Tang H, Atherton J, Cairns NJ (2008) Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy. J Neural Transm 115:1661–1671

    Article  PubMed  CAS  Google Scholar 

  52. Troakes C, Maekawa S, Wijesekera L, Rogelj B, Siklos L, Bell C, Smith B, Newhouse S, Vance C, Johnson L, Hortobagyi T, Shatunov A, Al-Chalabi A, Leigh N, Shaw CE, King A, Al-Sarraj S (2011) An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology. doi:10.1111/j.1440-1789.2011.01286.x

    Google Scholar 

  53. Van Damme P, Veldink JH, van Blitterswijk M, Corveleyn A, van Vught PW, Thijs V, Dubois B, Matthijs G, van den Berg LH, Robberecht W (2011) Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology 76:2066–2072

    Article  PubMed  Google Scholar 

  54. Van Langenhove T, van der Zee J, Engelborghs S, Vandenberghe R, Santens P, Van den Broeck M, Mattheijssens M, Peeters K, Nuytten D, Cras P, De Deyn PP, De Jonghe P, Cruts M, Van Broeckhoven C (2012) Ataxin-2 polyQ expansions in FTLD-ALS spectrum disorders in Flanders-Belgian cohorts. Neurobiol Aging 33:1004e17–20

    Google Scholar 

  55. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Min Min Lu and Lan Cheng for help with immunohistochemistry. This work was supported by NIH Director’s New Innovator Award 1DP2OD004417 (A.D.G.), NIH grants 1R01NS065317 and 1R01NS073660 (A.D.G.) and AG032953 (J.Q.T. and V.M.Y.L). A.D.G. is a Pew Scholar in the Biomedical Sciences, supported by The Pew Charitable Trusts, and a Rita Allen Foundation Scholar. M.P.H. is supported by a NIH Ruth L. Kirschstein NRSA predoctoral fellowship 5F31NS074848-02. JB is supported by a grant of the Deutsche Forschungsgemeinschaft DFG (AOBJ586910).

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  1. Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, M322 Alway Building, Stanford, CA, 94305, USA

    Michael P. Hart & Aaron D. Gitler

  2. Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Michael P. Hart

  3. Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Michael P. Hart

  4. Department of Pathology and Laboratory Medicine and the Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Johannes Brettschneider, Virginia M. Y. Lee & John Q. Trojanowski

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Correspondence to Aaron D. Gitler.

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Hart, M.P., Brettschneider, J., Lee, V.M.Y. et al. Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions. Acta Neuropathol 124, 221–230 (2012). https://doi.org/10.1007/s00401-012-0985-5

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