Differential HspBP1 expression accounts for the greater vulnerability of neurons than astrocytes to misfolded proteins

• Type of Material: Article
• Authors: Ting Zhao, Emory University; Yan Hong, Emory University; Peng Yin, Emory University; Shi Hua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2017-09-12
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2017, National Academy of Sciences. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1710549114
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 114
• Issue: 37
• Start Page: E7803
• End Page: E7811
• Grant/Funding Information: This work was supported by NIH Grants [NS101701 and NS036232 (to X.-J.L.) and NS095279 and NS095181 (to S.L.)] and the National Natural Science Foundation (91332206).
• Keywords: chaperone; Huntington; HEAT-SHOCK; PREFERENTIAL ACCUMULATION; NEURODEGENERATIVE DISEASES; GLIAL-CELLS; polyglutamine; Multidisciplinary Sciences; BRAIN; DEGENERATION; Science & Technology - Other Topics; neurodegeneration; STRESS-RESPONSE; UBIQUITIN LIGASE CHIP; HUNTINGTONS-DISEASE MICE; DEGRADATION; misfolding; Science & Technology
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Although it is well known that astrocytes are less vulnerable than neurons in neurodegenerative diseases, the mechanism behind this differential vulnerability is unclear. Here we report that neurons and astrocytes show markedly different activities in C terminus of Hsp70-interacting protein (CHIP), a cochaperone of Hsp70. In astrocytes, CHIP is more actively monoubiquitinated and binds to mutant huntingtin (mHtt), the Huntington’s disease protein, more avidly, facilitating its K48-linked polyubiquitination and degradation. Astrocytes also show the higher level and heat-shock induction of Hsp70 and faster CHIP-mediated degradation of various misfolded proteins than neurons. In contrast to astrocytes, neurons express abundant HspBP1, a CHIP inhibitory protein, resulting in the low activity of CHIP. Silencing HspBP1 expression via CRISPR-Cas9 in neurons ameliorated mHtt aggregation and neuropathology in HD knockin mouse brains. Our findings indicate a critical role of HspBP1 in differential CHIP/Hsp70 activities in neuronal and glial cells and the greater neuronal vulnerability to misfolded proteins in neurodegenerative diseases.