Piperine ameliorates SCA17 neuropathology by reducing ER stress

被引:38
作者
Guo, Jifeng [1 ,2 ,3 ]
Cui, Yiting [1 ,2 ,3 ]
Liu, Qiong [1 ,2 ,3 ]
Yang, Yang [1 ,2 ,3 ]
Li, Yujing [3 ]
Weng, Ling [1 ,2 ]
Tang, Beisha [1 ,2 ]
Jin, Peng [3 ]
Li, Xiao-Jiang [3 ,4 ]
Yang, Su [3 ]
Li, Shihua [1 ,2 ,3 ]
机构
[1] Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha 410008, Hunan, Peoples R China
[2] Cent S Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorder, Changsha 410008, Hunan, Peoples R China
[3] Emory Univ, Sch Med, Dept Human Genet, 615 Michael St, Atlanta, GA 30322 USA
[4] Jinan Univ, GHM Inst CNS Regenerat, Guangzhou 510631, Guangdong, Peoples R China
关键词
Polyglutamine; Ataxia; Neurotrophic factor; ER stress; ENDOPLASMIC-RETICULUM STRESS; TATA-BINDING PROTEIN; XBP1; MESSENGER-RNA; ATAXIA TYPE 17; NEUROTROPHIC FACTOR; TRANSCRIPTION FACTOR; HUNTINGTONS-DISEASE; EXPANDED POLYGLUTAMINE; TRINUCLEOTIDE REPEAT; PARKINSONS-DISEASE;
D O I
10.1186/s13024-018-0236-x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Background: Spinocerebellar ataxia 17 (SCA17) belongs to the family of neurodegenerative diseases caused by polyglutamine (polyQ) expansion. In SCA17, polyQ expansion occurs in the TATA box binding protein (TBP) and leads to the misfolding of TBP and the preferential degeneration in the cerebellar Purkinje neurons. Currently there is no effective treatment for SCA17. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a recently identified neurotrophic factor, and increasing MANF expression ameliorated SCA17 neuropathology in TBP-105Q knock-in (KI) mouse model, indicating that MANF could be a therapeutic target for treating SCA17. Methods: In this study, we screened a collection of 2000 FDA-approved chemicals using a stable cell line expressing luciferase reporter, which is driven by MANF promoter. We identified several potential candidates that can induce the expression of MANF. Of these inducers, piperine is an agent that potently induces the luciferase expression or MANF expression. Results: Addition of piperine in both cellular and mouse models of SCA17 alleviated toxicity caused by mutant TBP. Although mutant TBP is primarily localized in the nuclei, the polyQ expansion in TBP is able to induce ER stress, suggesting that nuclear misfolded proteins can also elicit ER stress as cytoplasmic misfolded proteins do. Moreover, piperine plays its protective role by reducing toxicity caused by the ER stress. Conclusion: Our study established piperine as a MANF-based therapeutic agent for ER stress-related neuropathology in SCA17.
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页数:13
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