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

ABSTRACT: 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 ?-synuclein, and this process in turn exacerbates toxicity of ?-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 ?-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 ?-synuclein in PD models. Also, oral administration of PARP1 inhibitor Veliparib prevented neurodegeneration and improved motor ability in ?-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.

SUBMITTER: Mao K 

PROVIDER: S-EPMC7294777 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature