Enzymes of sulfatide metabolism as new targets in healthy aging

衰老带来了“朊病毒样”蛋白的错误折叠、聚集和正常机体蛋白或肽的毒性。在本提案中，我们试图研究一种蛋白质错误折叠易感性新机制的重要性，该机制得到遗传证据的支持：硫脂代谢的变化（Platt等人2018，Gonzalez de San Roman等人2017，Han等人2007）。鞘脂是膜脂的主要种类。类结构典型地以18碳胺醇为基础，通常与脂肪酸和糖残基偶联，制成牛脑苷。脊椎动物的脑苷可以被脑苷磺酸转移酶硫酸盐化，生成硫脂，这是神经系统髓鞘的主要成分。我们发现，参与硫脂合成的唯一酶(脑苷硫转移酶（CST）酶（GAL3ST1基因）的一种常见氨基酸变体（V29M）会大大增加最常见朊病毒疾病的风险（Jones et al . 2020）。在这一提议中，我们提出了一个新的合作，将确定硫脂代谢的改变是否可以帮助我们理解蛋白质随着衰老而不受控制地错误折叠的倾向和/或它们对衰老神经细胞的毒性。医生和化学家之间的合作需要建立硫脂质测定，测量生物体液和组织中的硫脂质和其他鞘脂代谢物浓度，确定酶活性在显示蛋白质错误折叠的模型系统中的作用方向。

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.