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Nat Rev Neurol. 2010 Apr;6(4):211-20. doi: 10.1038/nrneurol.2010.18. Epub 2010 Mar 16.

TAR DNA-binding protein 43 in neurodegenerative disease.

Author information

1
Department of Neurology, University of Pennsylvania School of Medicine, 3600 Spruce Street, Philadelphia, PA 19104-4283, USA.

Abstract

In 2006, TAR DNA-binding protein 43 (TDP-43), a highly conserved nuclear protein, was identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and in the most common variant of frontotemporal lobar degeneration (FTLD), FTLD-U, which is characterized by cytoplasmic inclusions that stain positive for ubiquitin but negative for tau and alpha-synuclein. Since then, rapid advances have been made in our understanding of the physiological function of TDP-43 and the role of this protein in neurodegeneration. These advances link ALS and FTLD-U (now designated FTLD-TDP) to a shared mechanism of disease. In this Review, we summarize the current evidence regarding the normal function of TDP-43 and the TDP-43 pathology observed in FTLD-TDP, ALS, and other neurodegenerative diseases wherein TDP-43 pathology co-occurs with other disease-specific lesions (for example, with amyloid plaques and neurofibrillary tangles in Alzheimer disease). Moreover, we discuss the accumulating data that support our view that FTLD-TDP and ALS represent two ends of a spectrum of primary TDP-43 proteinopathies. Finally, we comment on the importance of recent advances in TDP-43-related research to neurological practice, including the new opportunities to develop better diagnostics and disease-modifying therapies for ALS, FTLD-TDP, and related disorders exhibiting TDP-43 pathology.

PMID:
20234357
PMCID:
PMC2892118
DOI:
10.1038/nrneurol.2010.18
[Indexed for MEDLINE]
Free PMC Article

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