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）基因的变异与广泛的神经退行性疾病有关。MAPT的点突变导致与17号染色体相关的帕金森病额颞叶痴呆（FTDP-17）， SNCA的三倍引起遗传性早发性帕金森病伴痴呆。这些罕见的变异已经被充分研究并对基因功能产生了相对较大的影响，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中常见的单倍型与阿尔茨海默病（AD）、进行性核上性麻痹（PSP）、皮质基底变性（CBD）和帕金森病（PD）的易感性相关。这些疾病中功能性MAPT风险变异的身份尚未确定，但在牛头病（AD、PSP和CBD）和PD之间似乎是不同的。同样，SNCA中常见的单倍型和二核苷酸重复多态性（REP1）通过尚不清楚的机制赋予PD风险。最后，AP0E*4等位基因是一个公认的AD易感因子，有证据表明AP0E*4等位基因可能增加PD患者痴呆的风险。因此，鉴于MAPT、SNCA和APOE在以帕金森病和/或痴呆为特征的多种疾病特征中发挥作用，这三个基因很可能影响PD中认知障碍（Cl）的发生和Cl的进展速度。我们进一步假设，MAPT和SNCA的遗传变异通过改变tau和α -突触核蛋白的表达或剪接异构体比例，介导了PD中Cl的发展和认知能力下降的速度。项目3将通过实现以下具体目标来检验这些假设：(1)通过对600名PD患者的横断面分析，确定MAPT、SNCA和APOE基因型或单倍型是否与认知功能相关；(2)通过对同一组PD患者进行纵向分析，确定MAPT、SNCA和APOE基因型或单倍型是否与认知能力下降率相关；(3)检测100名认知完整对照脑脊液中MAPT和SNCA基因型或单倍型与tau和α -突触核蛋白（总水平、磷酸化种类、同型比）的关系。最近PD遗传风险因素的发现揭示了丰富的信息，开辟了令人兴奋的新研究途径。发现PD中Cl的遗传风险因素的类似工作同样有希望，但仍然落后，主要是由于对认知特征良好的患者群体的访问有限。成功完成我们的目标将解决这一问题，所获得的知识有可能产生新的实验模型，发现有希望的治疗干预目标，并确定适合特定临床试验的患者亚组和风险受试者。

Variation within the MAPT (microtubule-associated protein tau) and SNCA (alpha-synuclein) genes is associated with a wide range of neurodegenerative disorders. Point mutations in MAPT result in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and triplications of SNCA cause hereditary early-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 susceptibility for Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Parkinson's disease (PD). The identity of the functional MAPT risk variants in these disorders has yet to be determined but appears to be distinct between the tauopathies (AD, PSP, and CBD) and PD. Similarly, common haplotypes and a dinucleotide repeat-polymorphism (REP1) in SNCA confer risk for PD through mechanisms that are not clearly 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 cognitive impairment (Cl) and the rate of progression of Cl in PD. We further hypothesize that genetic 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 cognitive function in a cross sectional analysis of 600 patients 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 patients with PD; (3) Examine the association of MAPT and SNCA genotypes or haplotypes with tau and alpha-synuclein (total levels, phosphorylated species, isoform ratios) in CSF from 100 cognitively 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 intervention, and identify subgroups of patients and at risk subjects appropriate for specific clinical trials.