脂筏
细胞生物学
下调和上调
生物
肌萎缩侧索硬化
原肌球蛋白受体激酶B
突变
信号转导
神经营养素
化学
神经营养因子
基因
遗传学
受体
内科学
医学
疾病
作者
Tobias Moll,Emily Graves,Agnieszka Urbanek,Nikita Soni,Ramya Ranganathan,Adrian Higginbottom,Shanshan Wang,Brian P. Head,Johnathan Cooper‐Knock,Pamela J. Shaw
标识
DOI:10.1101/2022.06.28.497990
摘要
Abstract Mutations within GLT8D1 contribute to familial amyotrophic lateral sclerosis. Pathogenic mutations impair GLT8D1 glycosyltransferase enzymatic function via a dominant negative mechanism, yet the downstream mechanism leading to neurotoxicity is unclear. Here we show that a p.R92C mutation causes fragmentation of the Golgi network and reduces ganglioside expression within membrane lipid rafts (MLRs), leading to impaired neurotrophin signalling. Expression of p.R92C-GLT8D1 in HEK293 cells and mouse primary neurons reduces expression of GM1 gangliosides within the cell plasma membrane leading to disruption of MLRs. Furthermore, p.R92C-GLT8D1 reduces TrkB-mediated pro-survival signalling in MLRs isolated from primary neurons. Interestingly, up-regulation of wild-type GLT8D1 enhances MLRs and promotes pro-survival signalling through TrkB. This closely mirrors findings for another ALS gene, CAV1 , suggesting convergence on a common pathogenic pathway. Other ALS genes have been associated with Golgi dysfunction and may disrupt the same pathway, suggesting a potential new therapeutic approach via upregulation of GLT8D1. Graphical Abstract
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