Synaptic dysglycosylation caused by the schizophrenia-risk variant in SLC39A8

项目摘要/摘要 精神分裂症是一种具有很强遗传性的严重精神疾病，遗传学的进步已经开始 解开这种疾病的复杂分子基础。GWAs已经确定了250多个与 精神分裂症在中枢神经系统神经元表达的基因附近富含，并参与突触生物学。 大多数与精神分裂症相关的变异都在基因组的非编码区，尽管有一小部分 导致已知蛋白质内的突变。精神分裂症中最显著的相关编码变异 Gwas是SLC39A8中的rs13107325，导致同名锰的错义突变(A391T (Mn2)传送器。SLC39A8的MN2转运是糖基化的关键，其酶促附着 碳水化合物转化为蛋白质和脂肪，这与神经发育和突触功能有关。 在这里，申请者将研究精神分裂症风险增加的一个新的分子机制。 A391T携带者使用小鼠模型进行遗传风险研究。已经证明A391T小鼠的糖基化发生了改变 突触蛋白，包括神经递质受体和细胞黏附分子，申请人将测试是否 这些蛋白质的糖基化改变了它们的运输和定位，补体的沉积，以及 额叶皮质中树突棘的数量(目标1)。接下来，他将尝试逆转之前确定的 口服补充Mn2会改变糖类，克服A391T对SLC39A8转运的损害。 这些研究将使用现有的基因工程小鼠品系，这是由 申请者，以及分析突触的尖端神经科学培训。这些目标加在一起，将 明确A391T在突触引起的分子改变，并为Mn2提供关键的临床前数据 在大脑发育和成熟的关键时期补充A391T载体。 申请者罗伯特·米勒博士完全有资格以他的背景进行拟议的实验 神经科学、精神病学遗传学和糖生物学。四年培训计划将促进发展 向独立调查员身份迈进，并生成未来R01所需的初步数据 具有明确治疗潜力的应用。他将继续与斯莫勒博士和 卡明斯在接受摩根·盛博士关于分子的额外培训和指导的同时 对突触的分析。他还邀请了大脑中的Mn2研究的世界领导者迈克尔·阿施纳博士和迈克尔·阿施纳博士。 Maurizio Fava，一位在精神药理学和试验设计方面拥有丰富经验的临床研究员，AS 他的研究顾问委员会的成员。最后，协作研究环境非常适合 促进申请者成为学术精神病学的独立研究人员的目标。

PROJECT SUMMARY/ABSTRACT Schizophrenia is a severe mental illness with strong heritability, and advances in genetics have started to unravel the complex molecular underpinnings of this disorder. GWAS have identified over 250 loci linked to schizophrenia which are enriched near genes expressed in CNS neurons and involved in synaptic biology. Most schizophrenia-associated variants are in the non-coding region of the genome, though a small number result in a mutation within a known protein. The most significantly associated coding variant in schizophrenia GWAS is rs13107325 in SLC39A8, resulting in a missense mutation (A391T) in the eponymous manganese (Mn2+) transporter. Mn2+ transport by SLC39A8 is critical for glycosylation, the enzymatic attachment of carbohydrates to proteins and lipids, which is involved in neurodevelopment and synaptic function. Here, the applicant will investigate a novel molecular mechanism underlying increased schizophrenia risk in A391T carriers using a mouse model of genetic risk. Having shown that A391T mice have altered glycosylation of synaptic proteins, including neurotransmitter receptors and cell adhesion molecules, the applicant will test if altered glycosylation of these proteins changes their trafficking and localization, deposition of complement, and the number of dendritic spines in the frontal cortex (Aim 1). Next, he will attempt to reverse previously identified glycome changes with oral Mn2+ supplementation, overcoming impaired SLC39A8 transport from A391T. These studies will employ existing genetically engineered mouse lines, glycobiology techniques pioneered by the applicant, and cutting-edge neuroscience training in analysis of the synapse. Together, these aims will define the molecular alterations caused by A391T at the synapse and provide critical preclinical data for Mn2+ supplementation in carriers of A391T during critical periods of brain development and maturation. The applicant, Dr. Robert Mealer, is well qualified to execute the proposed experiments with his background in neuroscience, psychiatric genetics, and glycobiology. The four-year training plan will foster development towards independent investigator status and generate the preliminary data necessary for a future R01 application with clear therapeutic potential. He will continue his mentee relationships with Drs. Smoller and Cummings, while receiving additional training and mentorship from Dr. Morgan Sheng on the molecular analysis of the synapse. He has also enlisted Dr. Michael Aschner, a world leader on Mn2+ in the brain, and Dr. Maurizio Fava, a clinician researcher with extensive experience in psychopharmacology and trial design, as members of his research advisory committee. Finally, the collaborative research environment is ideal for furthering the applicant’s goal of becoming an independent researcher in academic psychiatry.