Acta Neuropathologica

, Volume 124, Issue 2, pp 221–230

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

  • Michael P. Hart
  • Johannes Brettschneider
  • Virginia M. Y. Lee
  • John Q. Trojanowski
  • Aaron D. Gitler
Original Paper

DOI: 10.1007/s00401-012-0985-5

Cite this article as:
Hart, M.P., Brettschneider, J., Lee, V.M.Y. et al. Acta Neuropathol (2012) 124: 221. doi:10.1007/s00401-012-0985-5

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.

Keywords

TDP-43 Ataxin 2 Polyglutamine Amyotrophic lateral sclerosis 

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Michael P. Hart
    • 1
    • 2
    • 3
  • Johannes Brettschneider
    • 4
  • Virginia M. Y. Lee
    • 4
  • John Q. Trojanowski
    • 4
  • Aaron D. Gitler
    • 1
  1. 1.Department of GeneticsStanford University School of MedicineStanfordUSA
  2. 2.Department of Cell and Developmental BiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  3. 3.Neuroscience Graduate GroupPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  4. 4.Department of Pathology and Laboratory Medicine and the Center for Neurodegenerative Disease ResearchPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA