Enzymes of sulfatide metabolism as new targets in healthy aging

硫苷脂代谢酶作为健康衰老的新靶点

• 批准号: 2397310
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2397310
• 关键词: Enzymes; sulfatide; metabolism; new; targets

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.

衰老带来了“朊病毒样”蛋白质的错误折叠、聚集和正常身体蛋白质或肽的毒性。在这项提议中，我们试图研究一种新的蛋白质错误折叠易感性机制的重要性，该机制得到了遗传证据的支持：硫苷脂代谢的变化（Platt et al 2018，Gonzalez de San Roman et al 2017，Han et al 2007）。鞘脂是膜脂质的主要类别。该类结构通常基于18-碳胺醇，通常与脂肪酸和糖残基共轭以制备醋瑞布苷。脊椎动物中的脑苷脂可被神经鞘磷脂转移酶硫酸化，生成硫苷脂，硫苷脂是神经系统中髓鞘的主要成分。我们发现，参与硫苷脂合成的sole酶（糖苷磺基转移酶（CST）酶（GAL 3ST 1基因））的一种常见氨基酸变体（V29 M）可显著增加最常见朊病毒病的风险（Jones et al 2020）。在这项提案中，我们提出了一项新的合作，将建立硫苷脂代谢的改变是否可以帮助我们了解蛋白质不可控地错误折叠与衰老和/或其毒性老化神经细胞的倾向。需要医生和化学家之间的合作来建立硫苷脂的测定，测量生物流体和组织中的硫苷脂和其他鞘脂代谢物的浓度，确定显示蛋白质错误折叠的模型系统中酶活性的影响方向。