miR-25 alleviates polyQ-mediated cytotoxicity by silencing ATXN3

Fengzhen Huang; Li Zhang; Zhe Long; Zhao Chen; Xuan Hou; Chunrong Wang; Huirong Peng; Junling Wang; Jiada Li; Ranhui Duan; Kun Xia; De-Maw Chuang; Beisha Tang; Hong Jiang

doi:10.1016/j.febslet.2014.11.013

miR-25 alleviates polyQ-mediated cytotoxicity by silencing ATXN3

FEBS Lett. 2014 Dec 20;588(24):4791-8. doi: 10.1016/j.febslet.2014.11.013. Epub 2014 Nov 20.

Authors

Fengzhen Huang¹, Li Zhang², Zhe Long², Zhao Chen², Xuan Hou², Chunrong Wang², Huirong Peng², Junling Wang², Jiada Li³, Ranhui Duan³, Kun Xia³, De-Maw Chuang⁴, Beisha Tang⁵, Hong Jiang⁶

Affiliations

¹ Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Department of Neurology & Institute of Translational Medicine at University of South China, The First People's Hospital of Chenzhou, Chenzhou, PR China.
² Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
³ State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan 410078, PR China.
⁴ Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan 410078, PR China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, PR China.
⁶ Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan 410078, PR China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, PR China. Electronic address: jianghong73868@126.com.

Abstract

MicroRNAs (miRNAs) have been reported to play significant roles in the pathogenesis of various polyQ diseases. This study aims to investigate the regulation of ATXN3 gene expression by miRNA. We found that miR-25 reduced both wild-type and polyQ-expanded mutant ataxin-3 protein levels by interacting with the 3'UTR of ATXN3 mRNA. miR-25 also increased cell viability, decreased early apoptosis, and downregulated the accumulation of mutant ataxin-3 protein aggregates in SCA3/MJD cells. These novel results shed light on the potential role of miR-25 in the pathogenesis of SCA3/MJD, and provide a possible therapeutic intervention for this disorder.

Keywords: ATXN3; Cytotoxicity; Gene expression regulation; Neuronal intranuclear inclusion; Spinocerebellar ataxia type 3/Machado–Joseph disease; miR-25.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions / genetics
Ataxin-3
Base Sequence
Cell Survival / drug effects
Cell Survival / genetics
Cytotoxins / toxicity*
Gene Silencing*
HEK293 Cells
Humans
Machado-Joseph Disease / genetics
MicroRNAs / genetics*
Mutation
Nerve Tissue Proteins / deficiency*
Nerve Tissue Proteins / genetics*
Nuclear Proteins / deficiency*
Nuclear Proteins / genetics*
Peptides / toxicity*
Repressor Proteins / deficiency*
Repressor Proteins / genetics*

Substances

3' Untranslated Regions
Cytotoxins
MIRN25 microRNA, human
MicroRNAs
Nerve Tissue Proteins
Nuclear Proteins
Peptides
Repressor Proteins
polyglutamine
ATXN3 protein, human
Ataxin-3

Grants and funding

Z01 MH002698-13/Intramural NIH HHS/United States