Abstract
Misfolding and abnormal aggregation of α-synuclein (αSyn) have been shown to increase the risk of developing Parkinson's disease (PD). Finding some way to reduce the aggregation of αSyn is particularly important for the treatment of PD. The main route in prion-like αSyn 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 αSyn aggregation. The α7 nicotinic acetylcholine receptors (α7-nAChRs) are one of the most abundant nAChRs in the mammalian brain. Using nicotine and a selective α7-nAChRs agonist PNU-282987, we found a protective effect of α7-nAChRs on the cell damage induced by αSyn-PFF (preformed fibrils) through inhibiting apoptotic cell death. We further discovered an additive effect of α7-nAChRs on the clearance of αSyn in normal and αSyn stably transduced SH-SY5Y cells. Moreover, using α7-nAChRs knockout mice, we noticed that α7-nAChRs deficiency increased the deposition of αSyn and aggravated the loss of dopaminergic neurons in a chronic MPTP mouse model of PD. Our findings for the first time indicated that α7-nAChRs activation exhibited a neuroprotective effect on αSyn pathology and aggregation by promoting the clearance of αSyn.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s Disease (Nussbaum and Ellis, 2003)
To determine the involvement of α7-nicotinic acetylcholine receptors (nAChRs) in αSyn pathology, we investigated the effects of PNU-289287 and nicotine on αSyn-PFF-induced cell injury
In SH-SY5Y cells, αSyn-PFF (134.3 ± 10.2%, p = 0.0398) and MPP+ (138.6 ± 5.5%, p = 0.0145) increased Lactate Dehydrogenase (LDH) leakage compared to the control cells, while pretreatment with PNU-282987 (0.01 μM: 108.4 ± 6.3 %, p = 0.2267; 0.1 μM: 98.0 ± 3.2 %, p = 0.0251; 1 μM: 83.7 ± 10.4 %, p = 0.0008) or nicotine (0.01 μM: 107.2 ± 2.8 %, p = 0.1816; 0.1 μM: 101.2 ± 2.1%, p = 0.0522; 1 μM: 88.4 ±10.38 %, p = 0.0022) attenuated this LDH leakage in a dose-related manner compared to the αSyn-PFF group (Figure 1B)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s Disease (Nussbaum and Ellis, 2003). This disease is more common in the elderly, and the prevalence increases with age. LBs and LNs are intraneuronal inclusions composed of α-synuclein (αSyn) aggregates. Numerous studies have shown that αSyn misfolding and abnormal aggregation can cause severe damage to neurons and other cells, leading to mitochondrial damage (Devi et al, 2008; Luth et al, 2014), endoplasmic reticulum stress (Colla et al, 2012), synaptic dysfunction (Huang et al, 2019), autophagy, and lysosomal dysfunction (Nguyen et al, 2019). While misfolding and abnormal aggregation of αSyn is the pathological mechanisms of PD, finding some way to reduce the aggregation of αSyn is important for the treatment of PD
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