Intracellular Accumulation of α-Synuclein Aggregates Promotes S-Nitrosylation of MAP1A Leading to Decreased NMDAR-Evoked Calcium Influx and Loss of Mature Synaptic Spines.

Cortical synucleinopathies, including dementia with Lewy bodies and Parkinson's disease dementia, collectively known as Lewy body dementia, are characterized by the aberrant aggregation of misfolded α-synuclein (α-syn) protein into large inclusions in cortical tissue, leading to impairments in proteostasis and synaptic connectivity and eventually resulting in neurodegeneration. Here, we show that male and female rat cortical neurons exposed to exogenous α-syn preformed fibrils accumulate large, detergent-insoluble, PS129-labeled deposits at synaptic terminals. Live-cell imaging of calcium dynamics coupled with assessment of network activity reveals that aberrant intracellular accumulation of α-syn inhibits synaptic response to glutamate through NMDARs, although deficits manifest slowly over a 7 d period. Impairments in NMDAR activity temporally correlated with increased nitric oxide synthesis and S-nitrosylation of the dendritic scaffold protein, microtubule-associated protein 1A. Inhibition of nitric oxide synthesis via the nitric oxide synthase inhibitor l-NG-nitroarginine methyl ester blocked microtubule-associated protein 1A S-nitrosylation and normalized NMDAR-dependent inward calcium transients and overall network activity. Collectively, these data suggest that loss of synaptic function in Lewy body dementia may result from synucleinopathy-evoked nitrosative stress and subsequent NMDAR dysfunction. Significance Statement: This work shows the importance of the redox state of microtubule-associated protein 1A in the maintenance of synaptic function through regulation of NMDAR. We show that α-syn preformed fibrils promote nitric oxide synthesis, which triggers S-nitrosylation of microtubule-associated protein 1A, leading to impairment of NMDAR-dependent glutamate responses. This offers insight into the mechanism of synaptic dysfunction in Lewy body dementia.