title: Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.
abstract: OBJECTIVE
  Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations. Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies. We recently identified TDP-43 as the major pathological protein in sporadic ALS. In this study, we investigated TDP-43 in a larger series of ALS cases (n = 111), including familial cases with and without SOD1 mutations.
  
  
  METHODS
  Ubiquitin and TDP-43 immunohistochemistry was performed on postmortem tissue from sporadic ALS (n = 59), ALS with SOD1 mutations (n = 15), SOD-1-negative FALS (n = 11), and ALS with dementia (n = 26). Biochemical analysis was performed on representative cases from each group.
  
  
  RESULTS
  All cases of sporadic ALS, ALS with dementia, and SOD1-negative FALS had neuronal and glial inclusions that were immunoreactive for both ubiquitin and TDP-43. Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43. Biochemical analysis of postmortem tissue from sporadic ALS and SOD1-negative FALS demonstrated pathological forms of TDP-43 that were absent in cases with SOD1 mutations.
  
  
  CONCLUSIONS
  These findings implicate pathological TDP-43 in the pathogenesis of sporadic ALS. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. ian.mackenzie@vch.ca
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.forename: Felix
authors.initials: F
authors.lastname: Geser
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Mark S
authors.initials: MS
authors.lastname: Forman
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.forename: Heather
authors.initials: H
authors.lastname: Stewart
authors.forename: Andrew
authors.initials: A
authors.lastname: Eisen
authors.forename: Leo
authors.initials: L
authors.lastname: McClusky
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: Camelia M
authors.initials: CM
authors.lastname: Monoranu
authors.forename: J Robin
authors.initials: JR
authors.lastname: Highley
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008526:Medulla Oblongata / Q000473:pathology; D009044:Motor Cortex / Q000473:pathology; D009154:Mutation / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D025801:Ubiquitin / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; D025801:Ubiquitin; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1