TDP-43-mediated neurodegeneration: towards a loss-of-function hypothesis? - PubMed (original) (raw)

TDP-43-mediated neurodegeneration: towards a loss-of-function hypothesis?

Lies Vanden Broeck et al. Trends Mol Med. 2014 Feb.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically distinct fatal neurodegenerative disorders. Increasing molecular evidence indicates that both disorders are linked in a continuous spectrum (ALS-FTD spectrum). Neuronal cytoplasmic inclusions consisting of the nuclear TAR DNA-binding protein 43 (TDP-43) are found in the large majority of patients in the ALS-FTD spectrum and dominant mutations in the TDP-43 gene cause ALS. A major unresolved question is whether TDP-43-mediated neuronal loss is caused by toxic gain of function of cytoplasmic aggregates, or by a loss of its normal function in the nucleus. Here we argue that based on recent genetic studies in worms, flies, fish, and rodents, loss of function of TDP-43, rather than toxic aggregates, is the key factor in TDP-43-related proteinopathies.

Keywords: ALS; FTD; TDP-43; loss-of-function; neurodegeneration; proteinopathy.

Copyright © 2013 Elsevier Ltd. All rights reserved.

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