Disrupted glycosylation of lipids and proteins is a cause of neurodegeneration

Abstract

AbstractGlycosyltransferases represent a large family of enzymes that catalyse the biosynthesis of oligosaccharides, polysaccharides, and glycoconjugates. A number of studies have implicated glycosyltransferases in the pathogenesis of neurodegenerative diseases but differentiating cause from effect has been difficult. We have recently discovered that mutations proximal to the substrate binding site of glycosyltransferase 8 domain containing 1 (GLT8D1) are associated with familial amyotrophic lateral sclerosis (ALS). We demonstrated that ALS-associated mutations reduce activity of the enzyme suggesting a loss-of-function mechanism that is an attractive therapeutic target. Our work is the first evidence that isolated dysfunction of a glycosyltransferase is sufficient to cause a neurodegenerative disease, but connection between neurodegeneration and genetic variation within glycosyltransferases is not new. Previous studies have identified associations between mutations in UGT8 and sporadic ALS, and between ST6GAL1 mutations and conversion of mild cognitive impairment into clinical Alzheimer’s disease. In this review we consider potential mechanisms connecting glycosyltransferase dysfunction to neurodegeneration. The most prominent candidates are ganglioside synthesis and impaired addition of O-linked β-N-acetylglucosamine (O-GlcNAc) groups to proteins important for axonal and synaptic function. Special consideration is given to examples where genetic mutations within glycosyltransferases are associated with neurodegeneration in recognition of the fact that these changes are likely to be upstream causes present from birth.