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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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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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