Abstract
Activation of the alpha7 nicotinic acetylcholine receptor (α7nAchR) is regulated by prion protein (PrPC) expression and has a neuroprotective effect by modulating autophagic flux. In this study, we hypothesized that PrPC may regulate α7nAchR activation and that may prevent prion-related neurodegenerative diseases by regulating autophagic flux. PrP(106-126) treatment decreased α7nAchR expression and activation of autophagic flux. In addition, the α7nAchR activator PNU-282987 enhanced autophagic flux and protected neuron cells against PrP(106-126)-induced apoptosis. However, activation of autophagy and the protective effects of PNU-282987 were inhibited in PrPC knockout hippocampal neuron cells. In addition, PrPC knockout hippocampal neuron cells showed decreased α7nAchR expression levels. Adenoviral overexpression of PrPC in PrPC knockout hippocampal neuron cells resulted in activation of autophagic flux and inhibition of prion peptide-mediated cell death via α7nAchR activation. This is the first report demonstrating that activation of α7nAchR-mediated autophagic flux is regulated by PrPC, and that activation of α7nAchR regulated by PrPC expression may play a pivotal role in protection of neuron cells against prion peptide-induced neuron cell death by autophagy. These results suggest that α7nAchR-mediated autophagic flux may be involved in the pathogenesis of prion-related diseases and may be a therapeutic target for prion-related neurodegenerative diseases.
Highlights
Alpha-7 nicotinic acetylcholine receptors (α7nAchR), known as α7 nicotinic receptors, are a family of nicotinic acetylcholine receptors that regulate long-term memory and consist entirely of α7 subunits [1,2,3]
The protective effect and upregulation of autophagic flux caused by activating α7nAchR was suppressed by decreasing PrPC gene expression. These results suggest that α7nAchRmediated autophagic flux may be regulated via PrPC expression and that regulating PrPC expression is applicable as a therapeutic strategy for neurodegenerative disorders including prion disease
Cells were pretreated with Methyllycaconitine citrate salt (MLA) (50 nM, 12 hr) or PNU-282987 (1 μM, 12 hr) and were exposed to 50 μM PrP (106-126) for 12 h. that the results show that protein levels of α7nAChR decreased and those of LC3-II/LC3-I ratio and p62 increased following PrP (106-126) treatment
Summary
Alpha-7 nicotinic acetylcholine receptors (α7nAchR), known as α7 nicotinic receptors, are a family of nicotinic acetylcholine receptors that regulate long-term memory and consist entirely of α7 subunits [1,2,3] This receptor is distributed in the brain, endothelium, muscle and lymphocytes [2, 4,5,6]. Α7 nAChR antagonist, methyllycaconitine blocked the nicotine-mediated neuroprotective effect in differentiated PC-12 cells [15]. These data suggest that activation of α7nAchR is regulated by PrPC expression and may have a neuroprotective effect against neurodegenerative disorders by interacting with PrPC signals
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