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）基因内的变异是 与多种神经退行性疾病有关。MAPT中的点突变导致 与17号染色体连锁的额颞叶痴呆伴帕金森综合征（FTDP-17）和SNCA三联症 会导致遗传性早发性帕金森症和痴呆这些罕见的变异已经得到了很好的研究， 对基因功能的相对大的影响，包括改变剪接异构体比率（tau）和增加 野生型蛋白质（SNCA）的表达。MAPT中常见的单倍型与可重复性相关 用于阿尔茨海默病（AD）、进行性核上性麻痹（PSP）、皮质基底节变性（CBD）和 帕金森病（PD）。这些疾病中功能性MAPT风险变异的身份尚未确定。 确定，但似乎在tau蛋白病（AD，PSP和CBD）和PD之间是有区别的。同样， SNCA中常见的单倍型和二核苷酸重复多态性（REP 1）通过以下途径赋予PD风险： 机制还不清楚。最后，AP 0 E *4等位基因是一个公认的易感性 AD的因素，并且有一些证据表明它可能会增加PD中痴呆的风险。因此，鉴于 MAPT、SNCA和APOE在以帕金森综合征和/或帕金森综合征为特征的多种疾病特征中发挥作用。 这三个基因可能很好地影响认知障碍（CI）的发生和痴呆的发生率。 PD中Cl的进展。我们进一步假设MAPT和SNCA内的基因变异介导了 通过改变tau蛋白的表达或剪接异构体比例，导致PD患者发生CI和认知能力下降 和α-突触核蛋白。项目3将通过实现以下具体目标来测试这些假设：（1） 确定MAPT、SNCA和APOE基因型或单倍型是否与认知功能相关 对600例PD患者进行横断面分析：（2）测定MAPT、SNCA、APOE 基因型或单倍型与认知能力下降的速度相关， （3）研究MAPT和SNCA基因型或单倍型与PD的相关性。 从100名认知功能正常的人中，CSF中的tau和α-突触核蛋白（总水平，磷酸化种类，亚型rafios） 完整的对照品。最近发现的帕金森病遗传风险因素揭示了丰富的信息， 开辟了令人兴奋的新研究途径。类似的工作，以发现遗传风险因素的氯在PD是 同样有前途，但已经落后，主要是由于有限的获得认知良好的特点， 患者人群。成功完成我们的目标将解决这个问题，所获得的知识 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亚组和风险受试者。 相关性（参见说明）： PD患者认知功能障碍（Cl）的现有治疗方案获益有限， 非常需要改进的治疗策略。申请中提出的工作具有 有可能增加我们对PD中Cl的遗传过程的理解。这些知识 可能有助于确定新的治疗靶点，可用于预防和更好地治疗这种致残性疾病。 关于PD

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.