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

Qiong Liu, Shanshan Huang, Peng Yin, Su Yang, Jennifer Zhang, Liang Jing, Siying Cheng, Beisha Tang, Xiao-Jiang Li, Yongcheng Pan () and Shihua Li ()
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Qiong Liu: Central South University
Shanshan Huang: Huazhong University of Science and Technology
Peng Yin: Jinan University
Su Yang: Jinan University
Jennifer Zhang: Emory University School of Medicine
Liang Jing: Huazhong University of Science and Technology
Siying Cheng: Central South University
Beisha Tang: Central South University
Xiao-Jiang Li: Jinan University
Yongcheng Pan: Central South University
Shihua Li: Jinan University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14931-8

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