当前位置: X-MOL 学术Neuron › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological α-Synuclein Insult.
Neuron ( IF 14.7 ) Pub Date : 2019-12-18 , DOI: 10.1016/j.neuron.2019.12.004
Michael X Henderson 1 , Samantha Sedor 1 , Ian McGeary 1 , Eli J Cornblath 2 , Chao Peng 1 , Dawn M Riddle 1 , Howard L Li 1 , Bin Zhang 1 , Hannah J Brown 1 , Modupe F Olufemi 1 , Danielle S Bassett 3 , John Q Trojanowski 1 , Virginia M Y Lee 1
Affiliation  

Mutations in the GBA1 gene are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal lipid hydrolase glucocerebrosidase (GCase), and its activity has been linked to accumulation of α-synuclein. The current study systematically examines the relationship between GCase activity and both pathogenic and non-pathogenic forms of α-synuclein in primary hippocampal, cortical, and midbrain neuron and astrocyte cultures, as well as in transgenic mice and a non-transgenic mouse model of PD. We find that reduced GCase activity does not result in aggregation of α-synuclein. However, in the context of extant misfolded α-synuclein, GCase activity modulates neuronal susceptibility to pathology. Furthermore, this modulation does not depend on neuron type but rather is driven by the level of pathological α-synuclein seeds. This study has implications for understanding how GBA1 mutations influence PD pathogenesis and provides a platform for testing novel therapeutics.

中文翻译:

葡萄糖脑苷脂酶活性调节神经元对病理性α-突触核蛋白损伤的敏感性。

GBA1基因突变是帕金森氏病(PD)和路易体痴呆(DLB)的最常见遗传风险因素。GBA1编码溶酶体脂质水解酶葡萄糖脑苷脂酶(GCase),其活性与α-突触核蛋白的积累有关。当前的研究系统地检查了原发海马,皮层和中脑神经元和星形胶质细胞培养物中,以及转基因小鼠和PD的非转基因小鼠模型中,GCase活性与α-突触核蛋白的致病性和非致病性形式之间的关系。 。我们发现降低的GCase活性不会导致α-突触核蛋白的聚集。然而,在现有的错误折叠的α-突触核蛋白的情况下,GCase活性调节神经元对病理的敏感性。此外,这种调节不取决于神经元类型,而是由病理性α-突触核蛋白种子水平驱动。这项研究对于理解GBA1突变如何影响PD发病机理具有重要意义,并为测试新型疗法提供了平台。
更新日期:2019-12-30
down
wechat
bug