Journal
CURRENT OPINION IN NEUROLOGY
Volume 21, Issue 6, Pages 693-700Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/WCO.0b013e3283168d1d
Keywords
amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal lobar degeneration with ubiquitinated inclusions; transactive response DNA-binding protein-43
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Funding
- Canadian Institutes for Health Research [135169, 179009]
- Pacific Alzheimer Research Foundation [C06-01]
- National Institutes of Health [P50 AG 16574]
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Purpose of review We examine current evidence that the transactive response DNA-binding protein (TDP-43) plays a pathogenic role in both amyotrophic lateral sclerosis and frontotemporal dementia. Recent findings TDP-43 was recently identified as the major pathological protein in sporadic amyotrophic lateral sclerosis and in the most common pathological subtype of frontotemporal dementia, frontotemporal lobar degeneration with ubiquitinated inclusions. In these conditions, abnormal C-terminal fragments of TDP-43 are ubiquitinated, hyperphosphorylated and accumulate as cellular inclusions in neurons and glia. Cells with inclusions show absence of the normal nuclear TDP-43 localization. Recently, missense mutations in the gene encoding TDP-43 have been identified in patients with sporadic and familial amyotrophic lateral sclerosis. Summary The recent discovery of pathological TDP-43 in both amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions confirms that these are closely related conditions within a new biochemical class of neurodegenerative disease, the TDP-43 proteinopathies.
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