TAR DNA-binding protein 43 in neurodegenerative disease.

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.

• Authors: Alice S Chen-Plotkin, Virginia M-Y Lee, John Q Trojanowski
• Journal: Nature reviews. Neurology (Nat Rev Neurol) Vol. 6 Issue 4 Pg. 211-20 (Apr 2010) ISSN: 1759-4766 [Electronic] England
• PMID: 20234357 (Publication Type: Journal Article, Review)

Chemical References

• DNA-Binding Proteins

Topics

• Animals
• DNA-Binding Proteins (genetics, metabolism)
• Humans
• Neurodegenerative Diseases (genetics, metabolism, pathology)