Genetic Rosk Factors for Cognitive Impairment in Parkinson's Disease

MAPT(微管相关蛋白tau)和SNCA(α-突触核蛋白)基因的变异是 与广泛的神经退行性疾病有关。MAPT中的点突变导致 17号染色体连锁帕金森综合征(FTDP-17)与SNCA三联反应 导致遗传性早发性帕金森症和痴呆症。这些罕见的变种已经得到了充分的研究和 对基因功能的相对较大的影响，包括改变剪接异构体比率(Tau)和增加 野生型蛋白(SNCA)的表达。MAPT中常见的单倍型与易感性相关 用于阿尔茨海默病(AD)、进行性核上性麻痹(PSP)、皮质基底膜变性(CBD)和 帕金森氏病(PD)。这些疾病中功能性MAPT风险变异体的身份尚未确定 确定，但似乎是不同的牛磺酸疾病(AD，PSP，和CBD)和PD。同样， SNCA中常见的单倍型和二核苷酸重复多态(REP1)通过以下途径增加帕金森病的风险 机制还不是很清楚。最后，AP0E*4等位基因是公认的易感基因。 AD的因素，有一些证据表明，它可能会增加帕金森病患者患痴呆症的风险。因此，鉴于 MAPT、SNCA和APOE在以帕金森症和/或帕金森病为特征的多种疾病特征中发挥作用 痴呆，这三个基因可能会很好地影响认知损害(CL)的发生和 氯在帕金森病中的进展。我们进一步假设，MAPT和SNCA内的基因变异介导了 改变tau蛋白的表达或剪接异构体比例对帕金森病认知功能减退的影响 和α-突触核蛋白。项目3将通过实现以下具体目标来检验这些假设：(1) 确定MAPT、SNCA和APOE基因或单倍型是否与认知功能相关 在对600例帕金森病患者的横断面分析中；(2)确定MAPT、SNCA和APOE 在纵向分析中，基因或单倍型与认知减退率相关 对帕金森病患者进行队列分析；(3)用 100名认知受试者脑脊液中tau和α-突触核蛋白(总水平、磷酸化物种、亚型) 完整的对照。最近发现的帕金森病的遗传风险因素揭示了大量信息， 开辟了令人兴奋的研究新途径。发现帕金森病中氯离子遗传风险因素的类似工作是 同样有希望，但一直落后，主要是因为获得认知良好特征的机会有限 患者群体。我们的目标的成功完成将解决这个问题，所获得的知识已经 有可能产生新的实验模型，发现有希望的治疗干预靶点， 并确定适合于特定临床试验的患者和高危亚群。 相关性(请参阅说明)： 现有的治疗帕金森病认知障碍(CL)的方法益处有限， 改善治疗策略是非常必要的。申请中提出的工作具有 有可能增加我们对帕金森病中氯的遗传过程的理解。这一知识 可能有助于确定可用于预防和更好地治疗这种残疾的新的治疗靶点 帕金森病的各方面。

Variation within the MAPT (microtubule-associated protein tau) and SNCA (alpha-synuclein) genes is associated with a wide range of neurodegenerative disorders. Point mutafions in MAPT result in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and triplications of SNCA cause hereditary eariy-onset parkinsonism with dementia. These rare variants have well-studied and relatively large effects on gene function that include altering splice isoform ratios (tau) and increasing expression of wild-type protein (SNCA). Common haplotypes across MAPT are associated with suscepfibility for Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Parkinson's disease (PD). The identity of the funcfional MAPT risk variants in these disorders has yet to be determined but appears to be disfinct between the tauopathies (AD, PSP, and CBD) and PD. Similariy, common haplotypes and a dinucleotide repeat-polymorphism (REP1) in SNCA confer risk for PD through mechanisms that are not cleariy understood. Finally, the AP0E*4 allele is a well-established susceptibility factor for AD, and there is some evidence that it might increase risk for dementia in PD. Therefore, given that MAPT, SNCA, and APOE play a role in multiple disease traits characterized by parkinsonism and/or dementia, these three genes might well influence the occurrence of cognifive impairment (Cl) and the rate of progression of Cl in PD. We further hypothesize that genefic variation within MAPT and SNCA mediates the development of Cl and rate of cognitive decline in PD by altering expression or splicing isoform ratios of tau and alpha-synuclein. Project 3 will test these hypotheses by accomplishing the following specific aims: (1) Determine whether MAPT, SNCA, and APOE genotypes or haplotypes are associated with cognifive function in a cross secfional analysis of 600 pafients with PD; (2) Determine whether MAPT, SNCA, and APOE genotypes or haplotypes are associated with rate of cognitive decline in a longitudinal analysis of the same cohort of pafients with PD; (3) Examine the associafion of MAPT and SNCA genotypes or haplotypes with tau and alpha-synuclein (total levels, phosphorylated species, isoform rafios) in CSF from 100 cognifively intact controls. The recent discovery of genetic risk factors for PD has uncovered a wealth of information that has opened exciting new avenues of research. Similar work to discover genetic risk factors for Cl in PD is equally promising but has lagged behind, largely due to limited access to cognitively well-characterized patient populations. Successful completion of our Aims will address this issue and the knowledge gained has the potential to generate novel experimental models, discover promising targets for therapeutic intervenfion, and identify subgroups of pafients and at risk subiects appropriate for specific clinical trials. RELEVANCE (See instructions): Existing treatment options for cognitive impairment (Cl) in PD are of limited benefit and the development of improved therapeutic strategies is very much needed. The work proposed in the application has the potential to increase our understanding of the genetic processes that underiie Cl in PD. This knowledge might serve to identify novel therapeufic targets which could be used to prevent and better treat this disabling facet of PD.