PARP1 suppression by α7 nAChR activation attenuated α-synuclein-induced neurotoxicity in Parkinson's disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and recent studies have suggested that poly(ADP-ribose) polymerase-1 (PARP1) hyperactivation and the subsequent generation of poly(ADP-ribose) (PAR) polymers represent key steps in the formation of pathologic α-synuclein (α-syn) and consequent cell death. Finding approaches to inhibit PARP1 hyperactivation is particularly important for disease-modifying therapy in PD. The epidemiologic studies have suggested that nicotine in tobacco might exert neuroprotective effects by acting on nicotinic acetylcholine receptors (nAChRs), although its underlying mechanism is still illusive. Herein, we investigated the effects of the α7 nAChR on PARP1 hyperactivation in a α-syn fibril-induced PD model and explored the underlying mechanisms involved. We found that α7 nAChR activation played a role in suppressing PARP1 activation and PAR production, consequently reducing the α-syn aggregation and toxicity in vitro and in vivo. Characterization of the underlying mechanism revealed metabotropic-type signalling downstream of α7 nAChR, involving AKT1 phosphorylation and subsequently sirt6 proteasomal degradation, which, in turn, attenuated its positive regulatory effect on PARP1 activity, leading to a decrease in PAR abundance and pathologic α-syn aggregate formation. Furthermore, liquid chromatography‒mass spectrometry and related biochemical assays demonstrated that functional coupling between α7 nAChR and AKT1 was mediated by SRC, which physically interacts with α7 nAChR. Thus, the SRC/AKT1/sirt6 signalling cascade underpinned the cytoprotective role of α7 nAChR against the PARP1 hyperactivation caused by α-syn PFF. Since the PARP1 hyperactivation is predominantly implicated in α-syn neurodegeneration and other brain diseases, this study represents one step further toward developing α7-nAChR-mediated suppression of PARP1 activity as a promising therapeutic measure against neurodegeneration in related CNS diseases.