Harnessing post-translational regulation of SHANK3 as a boosting strategy for Phelan-McDermid syndrome

项目总结 大脑的正常发育需要精确的突触形成关键基因的剂量。基因的改变 通过功能缺失突变，如基因组缺失，或功能突变获得，如 基因组复制，导致大约50%的蛋白质含量变化。这通常会造成毁灭性的 对大脑发育和功能的影响。在一个例子中，显性的、功能丧失的突变 由SHANK3基因编码的突触后支架蛋白导致严重的神经发育 精神障碍，费兰-麦克德米德综合征。患有费兰-麦克德米德综合征的患者有中到重度 智力残疾，通常在生命的头两年出现发育迟缓。目前没有 针对这种疾病的靶向治疗。 这项建议旨在调查山克3的S翻译后调节，以增加基础知识 突触发育和生理，并为患有SHANK3突变的个体开发治疗途径。 在这个提案中，生物化学、行为学和神经生理学的结合将被用来解决 以下内容：1.确定体内抑制ERK2是否可以挽救由于 SHANK3单倍体功能不全。2.确定酪蛋白激酶抑制对SHANK3稳定性和 功能和3.鉴定调节SHANK3稳定性的蛋白酶体元件。 这项工作的影响将是通过翻译后理解SHANK3的动态调节 机制，发展对费兰-麦克德米德综合征治疗途径的临床前洞察 并开发一种分子方法来确定神经发育障碍的个性化治疗 对剂量敏感基因的突变。

PROJECT SUMMARY Proper brain development requires precise dosages of genes critical for synapse formation. Alterations of gene dosage through loss-of-function mutations, such as genomic deletions, or gain of function mutations, such as genomic duplications, result in approximately 50% change in protein content. This often has devastating consequences for brain development and function. In one example, dominant, loss-of-function mutations in the post-synaptic scaffolding protein encoded by the SHANK3 gene causes a severe neurodevelopmental disorder, Phelan-McDermid syndrome. Individuals with Phelan-McDermid syndrome have moderate to severe intellectual disability with developmental delays often noted in the first two years of life. There are currently no targeted therapies for this disorder. This proposal aims to investigate SHANK3’s post-translational regulation to add fundamental knowledge of synaptic development and physiology and develop treatment avenues for individuals with SHANK3 mutations. In this proposal, a combination of biochemistry, behavior and neurophysiology will be utilized to address the following: 1. Determine if in vivo inhibition of ERK2 rescues molecular and behavioral abnormalities due to SHANK3 haploinsufficiency. 2. Determine the impact of Casein Kinase inhibition on SHANK3 stability and function and 3. Identify the proteasomal elements which regulate SHANK3 stability. The impact of this work will be to understand the dynamic regulation of SHANK3 through post-translational mechanisms, develop pre-clinical insight into therapeutic treatment avenues for Phelan-McDermid syndrome and develop a molecular approach for identifying personalized therapies for neurodevelopmental disorders due to mutations in dosage sensitive genes.