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

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

Cannabidiol Induces Autophagy to Protects Neural Cells From Mitochondrial Dysfunction by Upregulating SIRT1 to Inhibits NF-κB and NOTCH Pathways

“…Combined with the results of Cannabidiol's effect on oxidative stress, we demonstrated that Cannabidiol can reduce oxidative stress damage, eliminate the increase in misfolded α-synuclein and other proteins, induce autophagy, and alleviate mitochondrial dysfunction. Mitochondrial biogenesis is a key process in the maintenance of mitochondrial mass, SIRT1 is the main regulator of mitochondrial biogenesis (Mao et al, 2020). The increase of SIRT1 has been considered as a therapeutic strategy for PD, previous research showed that SIRT1 has neuroprotective effects in both in vivo and in vitro PD models (Li et al, 2020).…”

“…Mitochondrial biogenesis is a key process in the maintenance of mitochondrial mass, SIRT1 is the main regulator of mitochondrial biogenesis ( Mao et al, 2020 ). The increase of SIRT1 has been considered as a therapeutic strategy for PD, previous research showed that SIRT1 has neuroprotective effects in both in vivo and in vitro PD models ( Li et al, 2020 ).…”

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

“…Further, genetic deletion of PARP-1 (or its pharmacological inhibition) diminished ASN toxicity and loss of DA neurons, and also improved behavioral performance [93]. In another study, PARP-1 inhibition by Veliparib was found to attenuate ASN accumulation, protect DA neurons, and improve the motor ability of transgenic mice carrying the A53T mutation [94]. An important event connected with PARP-1 is its role in promoting nuclear factor kappa B (NF-κB) activation, as well as downstream pro-inflammatory mediator expression in microglia [95].…”

The role of PARP1 in neurodegenerative diseases and aging

“…Other PARP1-related mechanisms of PD include neuroinflammation, autophagy dysregulation, and abnormal sleep rhythm [38,90]. PARP1 mediates neuroinflammation of PD not only through regulation of NF-jB transcriptional activity, but also the migration of high mobility group box 1 (HMGB1).…”