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.

富含亮氨酸的重复激酶2（LRRK2）突变是遗传性帕金森氏病的因果关系，并依赖于年龄依赖性。该蛋白质是一种大型复合激酶，具有几种报道的蛋白质相互作用和Mutliple提出的功能。一些突变增加了激酶活性，该项目的总体目的是扩展我们先前的观察结果，即LRRK2的激酶活性在与该基因突变的发病机理相关性中很重要。 我们目前的工作包括对激酶结构域内外突变对激酶活性的影响。已经提出，GTP与LRRK2的ROC结构域的结合增加了激酶活性。但是，我们发现这可能不是鸟苷核苷酸与ROC结构域结合的直接效应。但是，ROC结构域中LRRK2中完全废除鸟苷核苷酸的能力的突变确实降低了激酶活性，这表明调节该区域可能存在结构性效应。我们目前正在通过检查激酶域外的其他突变，这些突变在激酶活性界面上具有相似的影响。 我们已经将对基因表达的兴趣与LRRK2突变模型相结合，尤其是集中于激酶结构域中的突变。已经提出，LRRK2可以通过多种方式调节基因表达，包括与microRNA加工酶的相互作用。这将预测LRRK2会对基因表达产生强大影响。但是，我们没有找到证据支持在转染的细胞系中，在LRRK2患者的成纤维细胞或LRRK2的大脑区域中表达在大脑其他部分在病理学中建立病理学的年龄。总体而言，这些数据表明，如果LRRK2影响基因表达，则可能是间接机制。