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

Qiong Liu,Siying Cheng,Yongcheng Pan,Shihua Li,Jennifer Zhang,Beisha Tang,Shanshan Huang,Peng Yin,Liang Jing,Xiao-Jiang Li,Su Yang

doi:10.1038/s41467-020-14931-8

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.

Highlights

Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine expansion in the TATA box-binding protein (TBP)
Using SCA17 knock-in mice that endogenously express mutant TBP, we found that INPP5A, a protein that is highly abundant in the cerebellum and functions as a terminator of the inositol 1,4,5-trisphosphate (IP3) second messenger[16,17,18], is downregulated
This issue can be addressed by using stereotaxic injection of adenoviral vector (AAV) expressing the same amounts of mutant TBP in different mouse brain regions, which can avoid the influence of intrinsically diverse expression levels of mutant TBP in distinct brain regions

Summary

Introduction

Spinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). Using SCA17 knock-in mice that endogenously express mutant TBP, we found that INPP5A, a protein that is highly abundant in the cerebellum and functions as a terminator of the inositol 1,4,5-trisphosphate (IP3) second messenger[16,17,18], is downregulated. This was caused by the abnormal binding of mutant TBP to the transcription factor SP1, leading to reduced Inpp5a transcription. These findings uncover a tissue-specific protein that plays a critical role in the pronounced pathology in the cerebellum and provide a therapeutic target in SCA diseases

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Conclusion