Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17

• Type of Material: Article
• Authors: Qiong Liu, Emory University; Shanshan Huang, Emory University; Peng Yin, Jinan University; Su Yang, Jinan University; Jennifer Zhang, Emory University; Liang Jing, Huazhong University of Science & Technology; Siying Cheng, Central South University; Beisha Tang, Central South University; Xiao-Jiang Li, Emory University; Yongcheng Pan, Central South University; Shihua Li, Emory University
• Language: English
• Date: 2020-02-27
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2020, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-14931-8
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 1101
• End Page: 1101
• Grant/Funding Information: This work was supported by the National Natural Science Foundation of China grants 81830032, 31872779 (to X.-J.L.), 81701281 (to Q.L.), 2016YFC1306000 (to B.T.), and 81501182 (to Y.P.) and grants from the National Institutes of Health (R01NS095181, NS095279, NS101701, AG019206).
• Keywords: Trinucleotide repeat; Receptors; Degeneration; Transcription; Gene; Multidisciplinary Sciences; Binding; Science & Technology - Other Topics; Disease; Neurodegeneration; Science & Technology; Polyglutamine
• Research Categories: Biology, Genetics; Biology, Neuroscience; Health Sciences, Pathology

Abstract

Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). The selective neurodegeneration in the cerebellum in SCA17 raises the question of why ubiquitously expressed polyQ proteins can cause neurodegeneration in distinct brain regions in different polyQ diseases. By expressing mutant TBP in different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP. In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration, and Inpp5a overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice. Our findings demonstrate the important contribution of a tissue-specific protein to the polyQ protein-mediated selective neuropathology.