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

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.

Glycosyltransferase 8 domain-containing protein 1 (GLT8D1) is a UDP-dependent galactosyltransferase

“…Potential candidates could be glycolipids, which are known to be relevant in signaling events associated with neurodegeneration 42 and cancer 43 . In this context, recent evidence indicated that GLT8D1 was relevant in ganglioside biosynthesis 16 . Glycoproteins could also constitute potential substrates; for example, the T-antigen and related structures are present in mucins with important roles in cancer 44 and sialylated T-antigen is abundantly expressed in brain tissue glycoproteins [45][46][47] , but the enzymes involved in their biosynthesis have been well-studied.…”

“…GLT8D1 is also associated with cancer: a mutation in GLT8D1 was found in soft tissue tumors 12 ; it was proposed as prognostic marker for melanoma 13 and gastric cancer where it correlated with tumor immunity markers 14 ; it promoted human glioblastoma cell migration 15 . More recently, evidence supported a role of GLT8D1 in neurotrophin signaling within membrane lipid rafts 16 .…”