Impact of actin binding protein Coronin 1C in the pathogenesis of Parkinson's disease

肌动蛋白结合蛋白 Coronin 1C 在帕金森病发病机制中的影响

• 批准号: 10392204
• 负责人: Birgitt Schuele
• 金额: $ 23.61万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392204
• 关键词: Actin-Binding Protein; Address; Affect; Age; Bradykinesia; Candidate Disease Gene; Cell Line; Cell physiology; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Cytoskeleton; Disease; Endoplasmic Reticulum; Endosomes; Engineered Gene; Engineering; Etiology; Family; Gene Expression; Genes; Genetic; Goals; Guanosine Triphosphate Phosphohydrolases; Human; Human Engineering; Hyperactivity; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Introns; LRRK2 gene; Lewy Body Disease; Lewy body pathology; Membrane; Mitochondria; Modeling; Modification; Molecular; Morphology; Mutation; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Onset of illness; Outcome; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathology; Pathway interactions; Pattern; Penetrance; Phenotype; Phosphorylation; Phosphotransferases; Point Mutation; Post-Translational Protein Processing; Proteins; Research; Risk; Risk Factors; Role; Signal Transduction; Single Nucleotide Polymorphism; Site; Symptoms; System; Testing; Tremor; Variant; alpha synuclein; base; coronin protein; disorder risk; gene repression; genetic risk factor; genetic testing; genetic variant; genome wide association study; genome-wide; in vitro Model; induced pluripotent stem cell; induced pluripotent stem cell technology; knock-down; loss of function; mitochondrial dysfunction; nerve stem cell; neuropathology; novel; overexpression; polygenic risk score; posture instability; rac1 GTP-Binding Protein; risk variant; tau Proteins; tau expression; therapeutic target; tool

Parkinson’s Disease (PD) is a progressive neurodegenerative disease and is commonly characterized by tremor, bradykinesia, stiffness, and postural instability. PD is estimated to be prevalent in 572 individuals per 100,000 individuals over 45, with an estimated 1.2 million cases in the US by 2030. While the exact cause of PD is not known, a multitude of factors, including environmental and genetic factors have been identified and attributed to increase the risk of developing PD. Many genetic forms of PD have been described in the last two decades in addition to risk genes identified through candidate gene studies and genome-wide association studies (GWAS) and over 90 independent genome-wide significant risk signals have been described. Such genetic forms allow for the identification of mechanisms and pathways, and they could become therapeutic targets when validated. The most common genetic forms of PD are mutations in the LRRK2 gene. LRRK2 is a multidomain protein with both a GTPase domain and a kinase enzymatic domain. While LRRK2-PD is thought to present with a more homogenous clinical and neuropathological pattern due to its single genetic cause, there are still striking differences among LRRK2-PD, which pose several critical questions: why is it that not all LRRK2 variant carriers develop PD (reduced penetrance)? Why can the age at disease onset be quite variable even within families (variable age at onset)? Why does the neuropathology vary between LRRK2-PD cases, even in cases with the same allelic variant (pleomorphic pathology)? In this project, we aim to develop a system to test genetic modifiers in the context of LRRK2-PD and we nominated a variant in the CORO1C gene, which was recently found in the first LRRK2 GWAS study. We will combine advanced Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and induced pluripotent stem cell (iPSC) technologies to edit a single point mutation and modulate gene expression of CORO1C. This will allow us to generate an isogenic panel of human iPSC lines, in which we edited a single point mutation and activate or inhibit CORO1C expression to probe for gain-or loss-of function phenotypes in healthy and LRRK2 human iPSC neurons. Our aims are: Aim 1: To derive such human CRISPR engineered iPSC tools; Aim 2: To assess to what extent CORO1C affects cellular function, and alpha-synuclein or tau expression and post translational modifications; Aim 3: To determine to what extent CORO1C has an impact on LRRK2 function. The outcomes will have a critical impact on defining new mechanisms related to neurodegeneration and functionally validate CORO1C as a new disease target for PD nominated by clinical research-based genome- wide association. This in vitro approach of up/down-regulation of genes from their endogenous loci combined with specific disease-associated SNP gene editing and could serve as a testbed to unravel the functional consequences of genetic risk factors as modifiers in PD and related Lewy body pathologies.

帕金森病（PD）是一种进行性神经退行性疾病，通常以震颤为特征，