Leucine rich repeat kinase 2 and dominantly inherited Parkinson disease

富含亮氨酸重复激酶 2 与显性遗传性帕金森病

• 批准号: 8335982
• 负责人: Mark Cookson
• 金额: $ 54.47万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8335982
• 关键词: Age; Binding; Biological Models; Brain Part; Brain region; Cell Line; Complex; Data; Enzymes; Fibroblasts; GTP Binding; Gene Expression; Genes; Genetic; Guanosine; Inherited; MicroRNAs; Modeling; Mutation; Nucleotides; Parkinson Disease; Pathogenesis; Pathology; Patients; Penetrance; Phosphotransferases; Process; Proteins; Reporting; Research; Work; age related; base; interest; leucine-rich repeat kinase 2; mutant; new therapeutic target; protein complex

Leucine rich repeat kinase 2 (LRRK2) mutations are causal for inherited Parkinsons disease with age-dependent penetrance. The protein is a large complex kinase with several reported protein interactions and mutliple proposed functions. Some mutations increase kinase activity, and the overall aim of this project is to extend our prior observations that kinase activity of LRRK2 is important in pathogenesis association with mutations in this gene. Our current work includes examination of the effects of mutations both inside and outside of the kinase domain on kinase activity. It has been suggested that GTP binding to the ROC domain of LRRK2 increases kinase activity. However, we have found instead that this is likely not a direct effect of binding of the guanosine nucleotide to the ROC domain. However, mutations in LRRK2 in the ROC domain that completely abolish the capacity to bind guanosine nucleotides do decrease kinase activity, suggesting that there may be structural effects of modulating this region. We are currently following this data up by examining other mutations outside of the kinase domain that have similar effects of limiting kinase activity. We have combined our interest in gene expression with models of LRRK2 mutation, particularly focusing on mutations in the kinase domain. It has been suggested that LRRK2 may modulate gene expression in a number of ways, including by interaction with microRNA processing enzymes. This would predict that LRRK2 would have strong effects on gene expression. However, we did not find evidence to support this idea in transfected cell lines, in fibroblasts from LRRK2 patients or from brain regions where LRRK2 is expressed taken at ages where pathology was established in other parts of the brain. Overall, these data suggest that if LRRK2 influences gene expression it is likely by indirect mechanisms.

亮氨酸富重复激酶2 （LRRK2）突变是具有年龄依赖外显率的遗传性帕金森病的原因。该蛋白是一种大型复杂激酶，具有几种已报道的蛋白相互作用和多种功能。一些突变会增加激酶活性，本项目的总体目标是扩展我们之前的观察，即LRRK2的激酶活性在该基因突变的发病机制中起重要作用。