GLT8D1 mutations cause amyotrophic lateral sclerosis via disruption of neurotrophin signalling within membrane lipid rafts

Moll, T.; Graves, E.; Urbanek, A.; Soni, N.; Ranganathan, R.; Higginbottom, A.; Wang, S.; Head, B.; Cooper-Knock, J.; Shaw, P. J.

doi:10.1101/2022.06.28.497990

bioRxiv · 10.1101/2022.06.28.497990

GLT8D1 mutations cause amyotrophic lateral sclerosis via disruption of neurotrophin signalling within membrane lipid rafts

Moll, T.·Graves, E.·Urbanek, A.·Soni, N.·Ranganathan, R.·Higginbottom, A.·Wang, S.·Head, B.·Cooper-Knock, J.·Shaw, P. J.

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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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/497990v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1992dc4org.highwire.dtl.DTLVardef@18be04eorg.highwire.dtl.DTLVardef@333216org.highwire.dtl.DTLVardef@11d76c5_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Moll, T., Graves, E., Urbanek, A., Soni, N., Ranganathan, R., Higginbottom, A., Wang, S., Head, B., Cooper-Knock, J., Shaw, P. J.. 2022-07-01. GLT8D1 mutations cause amyotrophic lateral sclerosis via disruption of neurotrophin signalling within membrane lipid rafts. https://doi.org/10.1101/2022.06.28.497990

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