Tau Degradation Pathways

University Of California Santa Barbara, Santa Barbara CA

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The tau protein in the Alzheimer neurofibrillary tangle has been recognized for many years as a substrate for ubiquitination. More recently impaired proteasomal degradation has emerged as a theme related to many neurodegenerative diseases. In all the diseases with ubiquitinated inclusions, the relationship of the impaired degradation to the clinical disease remains uncertain. The evidence on this issue spans from the idea that the inclusions harm cells for a variety of reasons from triggering apoptosis to sequestering proteins of the ubiquitin pathway to the opposite idea that the inclusions are protective against some more toxic protofibrillar form of a self-assembled protein. Our goal for this proposal is to identity the specific modifications of tau that trigger ubiquitination and the specific proteins in the pathway that lead to tau ubiquitination. The delineation of this pathway represents an initial step toward understanding the role of tau ubiquitination in the pathogenesis of Alzheimer's disease and the tauopathies. We have amassed considerable preliminary data in support of the aims. Briefly, these findings are (a) tau phosphorylation represents a recognition signal for the tau E3 ligase; (2) the tau E2 ubiquitin conjugating enzyme is UbcH5B; (3) the tau complex which undergoes ubiquitination includes several chaperone proteins and their presence suggests a pathway that involves the E3 ligase CHIP (carboxyl terminus of Hsc70-interacting protein); (4) having detected several chaperone proteins by mass spectroscopy CHIP was identified immunocytochemically in the fraction with tau ubiquitin ligase activity. Often the pathway to the proteasome requires a collaboration between the ubiquitin-proteasome and chaperone systems. Because chaperone proteins have been identified in screens that rescue cells containing inclusions, understanding this pathway may be critical to devising therapeutic opportunities. [unreadable] [unreadable]