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Review: Transactive response DNA‐binding protein 43 (TDP‐43): mechanisms of neurodegeneration
Author(s) -
Gendron T. F.,
Josephs K. A.,
Petrucelli L.
Publication year - 2010
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/j.1365-2990.2010.01060.x
Subject(s) - neurodegeneration , frontotemporal lobar degeneration , amyotrophic lateral sclerosis , ubiquitin , neuroscience , neurotoxicity , biology , function (biology) , dna damage , loss function , mechanism (biology) , microbiology and biotechnology , frontotemporal dementia , genetics , medicine , gene , phenotype , disease , dna , pathology , toxicity , dementia , philosophy , epistemology
T. F. Gendron, K. A. Josephs and L. Petrucelli (2010) Neuropathology and Applied Neurobiology 36, 97–112
Transactive response DNA‐binding protein 43 (TDP‐43): mechanisms of neurodegeneration Since the identification of phosphorylated and truncated transactive response DNA‐binding protein 43 (TDP‐43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin‐positive inclusions, and the discovery that mutations in the TDP‐43 gene cause ALS, much effort has been directed towards establishing how TDP‐43 contributes to the development of neurodegeneration. Although few in vivo models are presently available, findings thus far strongly support the involvement of abnormally modified TDP‐43 in promoting TDP‐43 aggregation and cellular mislocalization. Therefore, TDP‐43‐mediated neurotoxicity is likely to result from a combination of toxic gains of function conferred by TDP‐43 inclusions as well as from the loss of normal TDP‐43 function. Nonetheless, the exact neurotoxic TDP‐43 species remain unclear, as do the mechanism(s) by which they cause neuronal death. Moreover, little is currently known about the roles of TDP‐43, both in the nucleus and the cytoplasm, making it difficult to truly appreciate the detrimental consequences of aberrant TDP‐43 function. This review will summarize what is currently understood regarding normal TDP‐43 function and the involvement of TDP‐43 in neurodegeneration, and will also highlight some of the many remaining questions in need of further investigation.