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Alpha-synuclein fibrils impair calcium flux in cortical neurons through aberrant nitric oxide-mediated inhibition of NMDA receptor function

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Title: Alpha-synuclein fibrils impair calcium flux in cortical neurons through aberrant nitric oxide-mediated inhibition of NMDA receptor function
Author: Hallam, Ryan
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Ryan, Scott
Abstract: Cortical synucleinopathies, including Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD), are characterized by the aberrant aggregation of misfolded α-synuclein into large inclusions in cortical tissue, leading to impairments in proteostasis and synaptic connectivity. However, the mechanisms linking α-synuclein aggregation with synaptic dysfunction have been difficult to ascertain. Here, I show that cortical rat neurons exposed to exogenous α-synuclein pre-formed fibrils (PFFs) accumulate large, insoluble deposits which are resistant to enzymatic digestion. I found that α-synuclein aggregates disrupt glutamate-evoked calcium flux, spontaneous calcium transients, and neural network activity, and that this may due to selective impairment of NMDA receptors. Moreover, inhibition of nitric oxide synthase results in a rescue of glutamate-evoked calcium flux and neuronal network activity, suggesting that aberrant accumulation of nitric oxide may impair NMDA receptor function in cortical synucleinopathies, and hence loss of synaptic function in PDD and DLB may result from synucleinopathy-evoked nitrosative stress.
URI: http://hdl.handle.net/10214/17921
Date: 2020-04
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