title: Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions.
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.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, M322 Alway Building, Stanford, CA 94305, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hart
authors.forename: Johannes
authors.initials: J
authors.lastname: Brettschneider
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000067528:Ataxins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D019680:Trinucleotide Repeat Expansion
chemical_list: D000067528:Ataxins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine