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Activation of ?7-nAChRs Promotes the Clearance of ?-Synuclein and Protects Against Apoptotic Cell Death Induced by Exogenous ?-Synuclein Fibrils.

ABSTRACT: Misfolding and abnormal aggregation of ?-synuclein (?Syn) have been shown to increase the risk of developing Parkinson's disease (PD). Finding some way to reduce the aggregation of ?Syn is particularly important for the treatment of PD. The main route in prion-like ?Syn spreading is the cholinergic innervated vagus nervous system and central cholinergic neurons. Since the degenerative changes and death of cholinergic neurons also run through the pathological process of PD, we hypothesize an involvement of the cholinergic system in ?Syn aggregation. The ?7 nicotinic acetylcholine receptors (?7-nAChRs) are one of the most abundant nAChRs in the mammalian brain. Using nicotine and a selective ?7-nAChRs agonist PNU-282987, we found a protective effect of ?7-nAChRs on the cell damage induced by ?Syn-PFF (preformed fibrils) through inhibiting apoptotic cell death. We further discovered an additive effect of ?7-nAChRs on the clearance of ?Syn in normal and ?Syn stably transduced SH-SY5Y cells. Moreover, using ?7-nAChRs knockout mice, we noticed that ?7-nAChRs deficiency increased the deposition of ?Syn and aggravated the loss of dopaminergic neurons in a chronic MPTP mouse model of PD. Our findings for the first time indicated that ?7-nAChRs activation exhibited a neuroprotective effect on ?Syn pathology and aggregation by promoting the clearance of ?Syn.

SUBMITTER: Zhao J

PROVIDER: S-EPMC7947362 | biostudies-literature |

REPOSITORIES: biostudies-literature

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