Molecular Genetic Analysis of Lysosomal Storage Disorder Genes in PD

描述(由申请人提供)：我们假设葡萄糖脑苷酶基因和其他溶酶体基因在相同的生化途径中的突变，包括己糖氨酸酶A(HEXA)、鞘磷脂磷酸二酯酶1(SMPD1)和粘脂蛋白1(MCOLN1)可能会扰乱a-突触核蛋白的细胞加工和运输，并导致路易体的形成。在我们之前的研究R21，NS050487中，我们已经表明葡萄糖脑苷酶基因突变是帕金森病和路易体疾病的危险因素。在目前的应用中，我们建议继续我们对GBA基因的研究，并将检测另外三个溶酶体基因，在临床特征的PD患者和对照以及LBD脑库样本中，这些基因突变会导致溶酶体存储障碍，即HEXA(Tay Sachs)、SMPD1(Niemann Pick A和B型)和MCOLN1(粘脂症IV型)。有两个具体目标。在Aim1中，我们将鉴定4个溶酶体的遗传变异，包括GBA、HEXA、SMPD1和MCOLN1。首先，对于初步的基因分析，我们将使用来自纽约德系犹太人研究的一个发现集，该研究包括300个病例和300个对照(NY AJ，NS50487)。我们选择了德系犹太人的病例和对照作为发现集，因为他们是一个基因同质的群体，很可能比其他混合群体更强大。其次，我们将使用GEPD NS36630和核心PD NS36630的复制集，该复制集包括1504个病例和314个对照，将用于检查发现集中识别的变异的等位基因关联。第三，对于复制集中重要的等位基因，我们将结合发现集和复制集来估计风险。目标2的目标是进一步确定路易身体脑部尸检样本的特征。首先，我们将在NYBB提供的其他路易小体病例中确定其他突变携带者。其次，我们将测量有溶酶体基因突变的神经病理学定义的路易体病例与无突变和对照的路易体病例相比，除了鞘磷脂积累外，还测量酶活性(GBA、HEXA、SMPD1)或mRNA水平。其次，对有突变和无突变的路易体脑尸检样本进行的神经病理学评估将包括对大脑皮质、黑质、海马体和小脑中α-突触核蛋白阳性结构的定量和定性评估。公共卫生相关性：值得注意的是，最近的研究表明，溶酶体基因突变可能与帕金森病有关，溶酶体/自噬途径也与帕金森病的发病有关。本研究将有助于阐明溶酶体基因在帕金森病遗传易感性中的作用。

DESCRIPTION (provided by applicant): We hypothesize that mutations in the Glucocerebrosidase gene and other lysosomal genes in the same biochemical pathway including Hexosaminidase A (HEXA), Sphingomyelin phosphodiesterase 1 (SMPD1) and mucolipin 1 (MCOLN1) may disrupt the cellular processing and trafficking of a-Synuclein and lead to Lewy Body formation. In our previous study, R21, NS050487, we have shown that mutations in the glucocerebrosidase gene are risk factors for PD and Lewy body disease. In the current application we propose to continue our studies on the GBA gene and will examine three additional lysosomal genes, mutations in which cause lysosomal storage disorders, namely, HEXA (Tay Sachs), SMPD1 (Niemann Pick Type A and B) and MCOLN1 (Mucolipidosis type IV) in clinically characterized PD patients and controls and LBD brain bank samples. There are two specific aims. In Aim1 we will identify genetic variation in 4 lysosomal including GBA, HEXA, SMPD1 and MCOLN1. First, for initial gene analysis, we will use a discovery set from the NY Ashkenazi Jewish study consisting of 300 cases and 300 controls (NY AJ, NS50487). We have chosen Ashkenazi Jewish cases and controls as a discovery set because it is a genetically homogeneous population and is likely to be more powerful than other admixed populations. Second, We will use a replication set from GEPD NS36630 and CORE PD NS36630 that comprises 1504 cases and 314 controls which will be used to examine allelic association of variants identified in the discovery set. Third, for alleles that are significant in the replication set we will combine the discovery and replication sets to estimate risk. The goal of Aim 2 is to further characterize Lewy Body brain autopsy samples. First, we will identify additional mutation carriers in additional Lewy body cases that are available in the NYBB. Second, We will measure enzyme activity (GBA, HEXA, SMPD1) or mRNA levels in addition to sphingolipid accumulation in neuropathologically defined Lewy body cases with lysosomal gene mutations compared to Lewy body cases without mutations and controls. Second, neuropathological evaluation of Lewy body brain autopsy samples with and without mutations will include quantitative and qualitative evaluation of a-synuclein positive structures in cortex, SN, hippocampus and cerebellum. PUBLIC HEALTH RELEVANCE: Significantly, recent studies suggest that mutations in lysosomal genes may be associated with PD and the lysosomal/autophagic pathway has also been implicated in PD pathogenesis. This study will serve to clarify the role of lysosomal genes in genetic susceptibility to PD.