Characterization of SynGAP Mutations in Human Cognitive Disorders

人类认知障碍中 SynGAP 突变的表征

• 批准号: 10094253
• 负责人: Richard L Huganir
• 金额: $ 52.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094253
• 关键词: Affect; Animal Behavior; Behavior; Behavioral; Behavioral Assay; Biochemical; Bipolar Disorder; C2 Domain; CRISPR/Cas technology; Cognition; Cognition Disorders; Copy Number Polymorphism; Data; Dendritic Spines; Development; Disease; Drug Screening; Electrophysiology (science); Electroporation; Etiology; FMR1; FMRP; Frameshift Mutation; Functional disorder; GTPase-Activating Proteins; Generations; Genes; Genetic study; Genome; Glutamates; Human; Impairment; In Vitro; Intellectual functioning disability; Investigation; Knock-in Mouse; Lead; Ligands; Mediating; Mental disorders; MicroRNAs; Molecular; Morphogenesis; Mus; Mutation; Neuraxis; Neurodevelopmental Disorder; Neurons; Onset of illness; PH Domain; Patients; Phenotype; Phosphorylation Site; Protein Biosynthesis; Proteins; Risk; Risk Factors; Role; SH3 Domains; Schizophrenia; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic; Translations; Variant; Vertebral column; autism spectrum disorder; base; behavioral phenotyping; calmodulin-dependent protein kinase II; comorbidity; density; disorder risk; genome editing; genome wide association study; high throughput screening; human disease; improved; in utero; in vivo; in vivo Model; insight; mouse model; mutant mouse model; neural circuit; neuronal circuitry; neuropsychiatric disorder; novel therapeutic intervention; postsynaptic; real-time images; response; risk variant; small molecule; tool; transmission process

Project Summary Recent genome-wide association studies of Intellectual disability (ID), Autism spectrum disorder (ASD) and Schizophrenia (SCZ) have improved our understanding of the molecular and cellular basis of human cognitive diseases. Functional categorization of these genes has revealed a significant enrichment of mutations affecting glutamatergic synapse structure and function. One protein that has been shown to regulate glutamatergic synapses is SynGAP, a RasGAP that is a critical negative regulator of spine morphogenesis and synaptic plasticity via Ras-ERK and protein synthesis-dependent signaling pathways. De Novo deleterious SYNGAP mutations are estimated to account for approximately 1% of ID cases and are highly comorbid with ASD. SYNGAP variants have also been found to be a significant risk factor in other neuropsychiatric disorders including SCZ and bipolar disorder (BP). We recently identified SynGAP as one of the most potent regulators of synaptic size and/or number using a high-throughput screen of 200 SCZ-associated risk genes. In addition, we found that ID/ASD-associated SynGAP mutations also affect synaptic structure and function. These data support the notion that human SynGAP mutations might alter synaptic transmission and plasticity. To determine how disease-associated SynGAP mutations impact synaptic pathophysiology and behavior, we will first characterize the effect of SYNGAP disease risk variants on synapse structure and function using a combination of approaches including real time imaging, biochemical and electrophysiological techniques. Next, we will use CRISPR/Cas9 genome editing to generate mouse models carrying SynGAP mutations that precisely mimic human disease risk variants of SynGAP. With these mice we will determine whether they have differential plasticity, circuit and behavioral phenotypes. Finally, we will perform mechanism based drug screens to target disrupted SynGAP-regulated signal transduction pathways to discover small molecule(s) that can ameliorate synaptic and behavioral deficits. This proposed project would be the first systematic investigation of disease-associated SynGAP mutations on synaptic pathophysiology and animal behavior. These studies will allow us to gain insight into mechanisms underlying SynGAP-associated diseases and pave the way for novel therapeutic strategies.

项目摘要 最近的全基因组关联研究智力残疾（ID），自闭症谱系障碍（ASD）和 精神分裂症（SCZ）的研究提高了我们对人类认知功能的分子和细胞基础的理解。 疾病这些基因的功能分类揭示了显著丰富的突变， 突触的结构和功能。有一种蛋白质被证明可以调节 突触是SynGAP，一种RasGAP，是棘形态发生和突触形成的关键负调节因子。 通过Ras-ERK和蛋白质合成依赖性信号通路的可塑性。新的有害的SYNGAP 突变估计占ID病例的约1%，并且与ASD高度共病。 SYNGAP变异体也被发现是其他神经精神疾病的重要危险因素 包括SCZ和双相情感障碍（BP）。我们最近将SynGAP确定为最有效的调节剂之一 突触的大小和/或数量使用高通量筛选200 SCZ相关的风险基因。此外，本发明还提供了一种方法， 我们发现ID/ASD相关SynGAP突变也影响突触结构和功能。这些数据 支持人类SynGAP突变可能改变突触传递和可塑性的观点。到 为了确定疾病相关的SynGAP突变如何影响突触病理生理学和行为，我们将 首先使用一种新的方法来表征SYNGAP疾病风险变体对突触结构和功能的影响， 包括真实的时间成像、生物化学和电生理技术的方法的组合。接下来， 我们将使用CRISPR/Cas9基因组编辑来生成携带SynGAP突变的小鼠模型， 精确模拟人类疾病风险的SynGAP变体。我们将用这些老鼠来确定它们是否 差异可塑性，电路和行为表型。最后，我们将执行基于机制的药物 筛选靶向被破坏的SynGAP调节的信号转导途径，以发现 可以改善突触和行为缺陷该项目将是第一个系统的 研究疾病相关SynGAP突变对突触病理生理学和动物行为的影响。 这些研究将使我们能够深入了解SynGAP相关疾病的潜在机制， 新的治疗策略的方法。

项目成果

Context-dependent hyperactivity in syngap1a and syngap1b zebrafish autism models.

syngap1a 和 syngap1b 斑马鱼自闭症模型中的情境依赖性过度活跃。

• DOI: 10.1101/2023.09.20.557316
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Sumathipala,SureniH;Khan,Suha;Kozol,RobertA;Araki,Yoichi;Syed,Sheyum;Huganir,RichardL;Dallman,JuliaE
• 通讯作者: Dallman,JuliaE

Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection.

• DOI: 10.7554/elife.75707
• 发表时间: 2022-04-08
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Kilinc, Murat;Arora, Vineet;Creson, Thomas K.;Rojas, Camilo;Le, Aliza A.;Lauterborn, Julie;Wilkinson, Brent;Hartel, Nicolas;Graham, Nicholas;Reich, Adrian;Gou, Gemma;Araki, Yoichi;Bayes, Alex;Coba, Marcelo;Lynch, Gary;Miller, Courtney A.;Rumbaugh, Gavin
• 通讯作者: Rumbaugh, Gavin