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Author Notes:

Correspondence: syang33@emory.edu; sli@emory.edu

JFG, X-JL, SY and SL designed the experiments and interpreted the results and wrote the paper.

JFG, YTC, QL, YY, SY performed the experiments.

PJ and YL provided the drugs for screening the stable cell line.

LW, and BT contribute financial support and read the manuscript.

All authors read and approved the final manuscript.

We thank Marta Gaertig and Sarah Lee for assisting the mouse work.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

This work was supported by the NIH (R21 NS102913 and NS101701 to XJL, NS0951610 and NS095279 to SHL), National Ataxia Foundation (Postdoctoral Fellowship to SY) and the national Nature Science Foundaton of China (81400938 to Ling Weng).

We thank Xiangya Hospital for supporting Jifeng Guo’s study at Emory University in the USA.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • 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

Piperine ameliorates SCA17 neuropathology by reducing ER stress

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Journal Title:

Molecular Neurodegeneration

Volume:

Volume 13, Number 1

Publisher:

, Pages 4-4

Type of Work:

Article | Final Publisher PDF

Abstract:

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.

Copyright information:

© 2018 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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