Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje Cell degeneration in inducible SCA17 Mice

• Type of Material: Article
• Authors: Su Yang, Emory University; Shanshan Huang, Emory University; Marta A. Gaertig, Emory University; Xiao-Jiang Li, Emory University; Shihua Li, Emory University
• Language: English
• Date: 2014-01-22
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuron.2013.12.002
• Title of Journal or Parent Work: Neuron
• ISSN: 0896-6273
• Volume: 81
• Issue: 2
• Start Page: 349
• End Page: 365
• Grant/Funding Information: The work was supported by the National Institutes of Health (grants AG19206 and NS041669 to X.-J.L. and AG031153 and NS0405016 to S.L.).; This research project was supported in part by the Viral Vector Core and the Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience NINDS Core Facilities (grant P30NS055077) and the State Key Laboratory of Molecular Developmental Biology, China.
• Keywords: HSC70 Heat-Shock Proteins; Cells, Cultured; TATA-Box Binding Protein; Nerve Degeneration; Aging; Mutation; Estrogen Antagonists; Mice, Inbred C57BL; Disease Models, Animal; Gene Expression Regulation; Animals; Analysis of Variance; Tamoxifen; Mice; Mice, Transgenic; Immunoprecipitation; DNA-Binding Proteins; Purkinje Cells; Protein Kinase C; Nerve Growth Factors; Peptides; Transcription Factors
• Research Categories: Biology, Neuroscience; Biology, Genetics

Abstract

Although protein-misfolding-mediated neurodegenerative diseases have been linked to aging, how aging contributes to selective neurodegeneration remains unclear. We established spinocerebellar ataxia 17 (SCA17) knockin mice that inducibly express one copy of mutant TATA box binding protein (TBP) at different ages by tamoxifen-mediated Cre recombination. We find that more mutant TBP accumulates in older mouse and that this accumulation correlates with age-related decreases in Hsc70 and chaperone activity. Consistently, older SCA17 mice experienced earlier neurological symptom onset and more severe Purkinje cell degeneration. Mutant TBP shows decreased association with XBP1s, resulting in the reduced transcription of mesencephalic astrocyte-derived neurotrophic factor (MANF), which is enriched in Purkinje cells. Expression of Hsc70 improves the TBP-XBP1s interaction and MANF transcription, and overexpression of MANF ameliorates mutant TBP-mediated Purkinje cell degeneration via protein kinase C (PKC)-dependent signaling. These findings suggest that the age-related decline in chaperone activity affects polyglutamine protein function that is important for the viability of specific types of neurons.