GLT8D1 mutations cause amyotrophic lateral sclerosis via disruption of neurotrophin signalling within membrane lipid rafts
biorxiv(2022)
摘要
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.
![Figure][1]
### Competing Interest Statement
The authors have declared no competing interest.
[1]: pending:yes
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关键词
amyotrophic lateral sclerosis,membrane lipid rafts,neurotrophin,mutations
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