Poly (ADP-ribose) polymerase 1 inhibition prevents neurodegeneration and promotes α-synuclein degradation via transcription factor EB-dependent autophagy in mutant α-synucleinA53T model of Parkinson's disease

被引：43

作者：

Mao, Kanmin ^{[1
]}

Chen, Jialong ^{[1
]}

Yu, Honglin ^{[1
]}

Li, Huihui ^{[1
]}

Ren, Yixian ^{[1
]}

Wu, Xian ^{[1
]}

Wen, Yue ^{[1
]}

Zou, Fei ^{[1
]}

Li, Wenjun ^{[1
]}

机构：

[1] Southern Med Univ, Sch Publ Hlth, Guangdong Prov Key Lab Trop Dis Res, Dept Occupat Hlth & Occupat Med, Guangzhou, Peoples R China

来源：

AGING CELL | 2020年 / 19卷 / 06期

基金：

中国国家自然科学基金;

关键词：

autophagy; Parkinson's disease; PARP1; SIRT1; TFEB; NUCLEAR EXPORT;

D O I：

10.1111/acel.13163

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Poly (ADP-ribose) polymerase 1 (PARP1) is a master regulator of diverse biological processes such as DNA repair, oxidative stress, and apoptosis. PARP1 can be activated by aggregated alpha-synuclein, and this process in turn exacerbates toxicity of alpha-synuclein. This circle is closely linked to the evolution of Parkinson's disease (PD) that characterized by progressive neurodegeneration and motor deficits. Here, we reported the PARP1, as a novel upstream molecular of transcription factor EB (TFEB), participates in regulation of autophagy in alpha-synuclein aggregated cells and mice. PARP1 inhibition not only enhances the nuclear transcription of TFEB via SIRT1 mediated down-regulation of mTOR signaling but also reduces nuclear export of TFEB by attenuating the TFEB-CRM1 interaction. Our results revealed that PARP1 inhibition lessened the accumulation of alpha-synuclein in PD models. Also, oral administration of PARP1 inhibitor Veliparib prevented neurodegeneration and improved motor ability in alpha-synucleinA53T transgenic mice. These findings identify that PARP1 signaling pathway regulates TFEB-mediated autophagy, pointing to potential therapeutic strategy of PD via enhancing protein degradation systems.

引用

页数：14