Enzymes of sulfatide metabolism as new targets in healthy aging

Aging brings with it "prion-like" protein misfolding, aggregation and toxicity of normal body
proteins or peptides. In this proposal we seek to investigate the importance of a new
mechanism of susceptibility to protein misfolding, underpinned by genetic evidence: changes
in 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 on
an 18-carbon amine alcohol, often conjugated with a fatty acid and a sugar residue to make a
cerebroside. Cerebrosides in vertebrates may be sulphated by the cerebroside
sulfotransferase enzyme to make sulfatide, a dominant component of the myelin sheath in
the nervous system. We have discovered that a common amino acid variant (V29M) of the
sole 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 whether
alteration of sulfatide metabolism can help us understand the propensity for proteins to
uncontrollably mis-fold with aging and/or their toxicity to aging nerve cells. The collaboration
between a physician and a chemist is required to establish an assay for sulfatides, to
measure sulfatide and other sphingolipid metabolite concentrations in biofluids and tissues,
determine a direction of effect of enzyme activity in model systems that display protein
misfolding.