Enzymes of sulfatide metabolism as new targets in healthy aging

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Aging brings with it "prion-like" protein misfolding, aggregation and toxicity of normal bodyproteins or peptides. In this proposal we seek to investigate the importance of a newmechanism of susceptibility to protein misfolding, underpinned by genetic evidence: changesin sulfatide metabolism (Platt et al 2018, Gonzalez de San Roman et al 2017, Han et al 2007).Sphingolipids are a major class of membrane lipids. The class structure is typically based onan 18-carbon amine alcohol, often conjugated with a fatty acid and a sugar residue to make acerebroside. Cerebrosides in vertebrates may be sulphated by the cerebrosidesulfotransferase enzyme to make sulfatide, a dominant component of the myelin sheath inthe nervous system. We have discovered that a common amino acid variant (V29M) of thesole enzyme involved in the synthesis of sulfatide (cerebroside sulfotransferase (CST)enzyme (GAL3ST1 gene)) confers a strongly increased risk of the most common prion disease(Jones et al 2020). In this proposal we propose a new collaboration that will establish whetheralteration of sulfatide metabolism can help us understand the propensity for proteins touncontrollably mis-fold with aging and/or their toxicity to aging nerve cells. The collaborationbetween a physician and a chemist is required to establish an assay for sulfatides, tomeasure sulfatide and other sphingolipid metabolite concentrations in biofluids and tissues,determine a direction of effect of enzyme activity in model systems that display proteinmisfolding.