期刊
JOURNAL OF NEUROSCIENCE
卷 42, 期 50, 页码 9473-9487出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0074-22.2022
关键词
alpha-synuclein; MAP1A; NMDAR; Parkinson?s disease; S-nitrosylation; synapse
资金
- Canadian Institutes of Health Research [2014-685]
- Natural Sciences and Engineering Research Council of Canada [RG060805, CRDPJ 490841-15]
- Vanier Program
- CGSM
- PSSO
- OGS
Cortical synucleinopathies, characterized by the abnormal aggregation of α-synuclein protein, can lead to neurodegeneration. This study found that the exposure of rat cortical neurons to exogenous α-syn preformed fibrils resulted in the accumulation of insoluble deposits at synaptic terminals, inhibiting synaptic response to glutamate. These impairments in synaptic function may be correlated with nitric oxide synthesis and S-nitrosylation of dendritic scaffold protein.
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 a-synuclein (a-syn) protein into large inclusions in cort-ical 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 a-syn preformed fibrils accumulate large, detergent -insol-uble, PS129-labeled deposits at synaptic terminals. Live-cell imaging of calcium dynamics coupled with assessment of network activ-ity reveals that aberrant intracellular accumulation of a-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 syn-thesis 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据