Mutant Huntingtin Inhibits αB-Crystallin Expression and Impairs Exosome Secretion from Astrocytes

• Type of Material: Article
• Authors: Yan Hong, Emory University; Ting Zhao, Emory University; Xiao-Jiang Li, Emory University; Shi Hua Li, Emory University
• Language: English
• Date: 2017-09-27
• Publisher: American Association of Neuroscience Nurses; Lippincott Williams and Wilkins
• Publication Version: Final Published Version
• Copyright Statement: © 2017 the authors.
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.1418-17.2017
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0885-0395
• Volume: 37
• Issue: 39
• Start Page: 9550
• End Page: 9563
• Grant/Funding Information: This work was supported by National Institutes of Health NS036232 and NS101701 to X.-J.L., and Grants NS095279 and NS095181 to S.L.
• Keywords: αB-crystallin; exosome; Mice; Corpus Striatum; Huntington disease; release; Exosomes; Huntingtin Protein; Female; Mutation; Animals; Huntington Disease; Astrocytes; astrocytes; Cells, Cultured; Exocytosis; alpha-Crystallin B Chain; Male
• Research Categories: Biology, Genetics

Abstract

In the brain, astrocytes secrete diverse substances that regulate neuronal function and viability. Exosomes, which are vesicles produced through the formation of multivesicular bodies and their subsequent fusion with the plasma membrane, are also released from astrocytes via exocytotic secretion. Astrocytic exosomes carry heat shock proteins that can reduce the cellular toxicity of misfolded proteins and prevent neurodegeneration. Although mutant huntingtin (mHtt) affects multiple functions of astrocytes, it remains unknown whether mHtt impairs the production of exosomes from astrocytes. We found that mHtt is not present in astrocytic exosomes, but can decrease exosome secretion from astrocytes in HD140Q knock-in (KI) mice. N-terminal mHtt accumulates in the nuclei and forms aggregates, causing decreased secretion of exosomes from cultured astrocytes. Consistently, there is a significant decrease in secreted exosomes in both female and male HD KI mouse striatum in which abundant nuclear mHtt aggregates are present. Conversely, injection of astrocytic exosomes into the striatum of HD140Q KI mice reduces the density of mHtt aggregates. Further, mHtt in astrocytes decreased the expression of αB-crystallin, a small heat shock protein that is enriched in astrocytes and mediates exosome secretion, by reducing the association of Sp1 with the enhancer of the αB-crystallin gene. Importantly, overexpression of αB-crystallin rescues defective exosome release from HD astrocytes as well as mHtt aggregates in the striatum of HD140Q KI mice. Our results demonstrate that mHtt reduces the expression of αB-crystallin in astrocytes to decrease exosome secretion in the HD brains, contributing to non–cellautonomous neurotoxicity in HD.