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

• Authors: Ting Zhao, Emory University; Yan Hong, Emory University; Peng Yin, Emory University; Shi Hua Li, Emory University; Xiao-Jiang Li, Emory University
• Journal Title: Proceedings of the National Academy of Sciences
• Volume: Volume 114, Number 37
• Publisher: National Academy of Sciences | 2017-09-12, Pages E7803-E7811
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.1710549114
• Subjects: Biology, Genetics; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; polyglutamine; Huntington; chaperone; misfolding; neurodegeneration; HUNTINGTONS-DISEASE MICE; UBIQUITIN LIGASE CHIP; NEURODEGENERATIVE DISEASES; PREFERENTIAL ACCUMULATION; STRESS-RESPONSE; GLIAL-CELLS; HEAT-SHOCK; BRAIN; DEGENERATION; DEGRADATION

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.