Synaptic dysglycosylation caused by the schizophrenia-risk variant in SLC39A8

SLC39A8 中精神分裂症风险变异引起的突触糖基化异常

• 批准号: 10490354
• 负责人: Robert G Mealer
• 金额: --
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2022-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490354
• 关键词: Adolescence; Advisory Committees; Affect; Award; Biological; Biology; Brain; Brain Diseases; Carbohydrates; Carrier Proteins; Cell Adhesion Molecules; Cell-Adhesion Molecule Receptors; Chromosome Pairing; Clinical Trials; Code; Complement; Complex; Consultations; Data; Dendritic Spines; Deposition; Development; Diagnostic; Disease; Dopamine; Environment; Enzymes; Family; Follow-Up Studies; Fostering; Functional disorder; Future; Genes; Genetic; Genetic Risk; Genetically Engineered Mouse; Genome; Glutamate Receptor; Glycobiology; Glycoproteins; Goals; Heritability; Homeostasis; Human; Impairment; Individual; Instruction; Jordan; K-Series Research Career Programs; Knock-in Mouse; Laboratories; Lead; Length; Link; Lipids; Manganese; Membrane; Mendelian disorder; Mentorship; Metals; Methods; Missense Mutation; Molecular; Molecular Analysis; Mus; Mutation; Neurologic; Neurons; Neurosciences; Neurotransmitter Receptor; Oral; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Plasma; Play; Polysaccharides; Protein Glycosylation; Proteins; Proteomics; Psychiatry; Psychopharmacology; Research; Research Personnel; Residencies; Rodent; Role; Schizophrenia; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Supplementation; Synapses; Techniques; Testing; Therapeutic; Trace Elements; Training; Translating; Translations; Untranslated RNA; Variant; Vertebral column; Work; base; career; cofactor; confocal imaging; critical period; density; experience; experimental study; frontal lobe; gamma-Aminobutyric Acid; genetic association; genome wide association study; glycoproteomics; glycosylation; improved; insight; member; mouse model; neurodevelopment; neuropsychiatric disorder; neurotransmission; novel; novel therapeutics; post-doctoral training; pre-clinical; preclinical safety; psychogenetics; receptor; risk variant; schizophrenia risk; severe mental illness; synaptic function; synaptic pruning; trafficking; translational study; trial design

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.

项目总结/摘要 精神分裂症是一种严重的精神疾病，具有很强的遗传性，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，其在CNS神经元中表达的基因附近富集，并参与突触生物学。 大多数精神分裂症相关的变异都在基因组的非编码区，尽管数量很少。 导致已知蛋白质内的突变。精神分裂症中最显著相关的编码变异 GWAS是SLC 39 A8中的rs 13107325，导致表位锰 (Mn2+）运输机。SLC 39 A8的Mn 2+转运对于糖基化是至关重要的，糖基化是酶促连接的关键。 碳水化合物转化为蛋白质和脂质，参与神经发育和突触功能。 在这里，申请人将研究一种新的分子机制，这种机制是精神分裂症风险增加的基础。 A391 T携带者使用遗传风险的小鼠模型。已经显示A391 T小鼠具有改变的糖基化， 突触蛋白，包括神经递质受体和细胞粘附分子，申请人将测试 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， 额叶皮层中树突棘的数量（目标1）。下一步，他将试图扭转先前确定的 糖组随着口服Mn 2+补充而改变，克服了A391 T对SLC 39 A8转运的损害。 这些研究将采用现有的基因工程小鼠品系， 申请人，和尖端神经科学培训的突触分析。总之，这些目标将 定义A391 T在突触处引起的分子改变，并为Mn 2+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A391 T载体。 申请人Robert Mealer博士具有以下背景，完全有资格执行拟议的实验： 神经科学、精神遗传学和糖生物学。四年培训计划将促进发展 获得独立研究者地位，并生成未来R 01所需的初步数据 具有明确治疗潜力的应用。他将继续与Smoller博士的学员关系， 卡明斯，同时接受额外的培训和指导博士摩根盛的分子 突触的分析。他还邀请了大脑中Mn 2+的世界领导者Michael Aschner博士和Dr. Maurizio Fava是一名临床研究人员，在精神药理学和试验设计方面拥有丰富的经验， 他的研究顾问委员会成员。最后，合作研究环境是理想的， 促进申请人成为学术精神病学独立研究人员的目标。