Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations.
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.
Mackenzie
Ian R A
IR
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. ian.mackenzie@vch.ca
Bigio
Eileen H
EH
Ince
Paul G
PG
Geser
Felix
F
Neumann
Manuela
M
Cairns
Nigel J
NJ
Kwong
Linda K
LK
Forman
Mark S
MS
Ravits
John
J
Stewart
Heather
H
Eisen
Andrew
A
McClusky
Leo
L
Kretzschmar
Hans A
HA
Monoranu
Camelia M
CM
Highley
J Robin
JR
Kirby
Janine
J
Siddique
Teepu
T
Shaw
Pamela J
PJ
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
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
D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; D025801:Ubiquitin; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1