p62/sequestosome 1 binds to TDP-43 in brains with frontotemporal lobar degeneration with TDP-43 inclusions.

Abstract

Ubiquitin-positive cytoplasmic inclusions are consistently found in various neurodegenerative diseases. As with ubiquitin, anti-p62/SQSTM1 (referred to as p62) antibody clearly immunostains these inclusions. p62 has a ubiquitin-associated domain at the carboxyl terminus and thereby interacts with ubiquitinated and misfolded proteins. Here we immunoprecipitated endogenous p62 in the cerebral cortex from patients with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and found that p62 coimmunoprecipitated several proteins, including TDP-43, which is a major disease protein in FTLD-TDP. Unexpectedly, p62 immunoprecipitated a smaller amount of TDP-43 in FTLD-TDP compared with controls. Further analyses showed that p62 physiologically binds to TDP-43 and likely is involved in degradation of TDP-43 with 35-kDa, but not full-length TDP-43. Our results suggest that the interaction of TDP-43 and p62 is disrupted and may participate in the pathogenesis of TDP-43 proteinopathy.

• Authors: Kunikazu Tanji, Hai-Xin Zhang, Fumiaki Mori, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 90 Issue 10 Pg. 2034-42 (Oct 2012) ISSN: 1097-4547 [Electronic] United States
• PMID: 22674379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• DNA, Complementary
• DNA-Binding Proteins
• Indicators and Reagents
• RNA, Small Interfering
• SQSTM1 protein, human
• Sequestosome-1 Protein

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Blotting, Western
• Cell Line
• DNA, Complementary (biosynthesis, genetics)
• DNA-Binding Proteins (metabolism)
• Fluorescent Antibody Technique
• Frontotemporal Dementia (metabolism, pathology)
• HeLa Cells
• Humans
• Immunoprecipitation
• Inclusion Bodies (pathology)
• Indicators and Reagents
• Plasmids (genetics)
• Protein Binding
• RNA, Small Interfering (biosynthesis, genetics)
• Sequestosome-1 Protein
• Transfection