Molecular Genetic Analysis of Lysosomal Storage Disorder Genes in PD

描述（由申请人提供）：我们假设糖脑苷酶基因和其他在同一生化途径中的溶酶体基因的突变，包括己糖胺酶A （HEXA）、鞘磷脂磷酸二酯酶1 （SMPD1）和粘磷脂1 (MCOLN1)，可能会破坏A - synuclein的细胞加工和运输，导致路易体的形成。在我们之前的研究R21， NS050487中，我们已经证明糖脑苷酶基因突变是PD和路易体病的危险因素。在目前的申请中，我们建议继续我们对GBA基因的研究，并将在临床特征PD患者和对照组以及LBD脑库样本中检测另外三个导致溶酶体储存障碍的溶酶体基因，即HEXA (Tay Sachs), SMPD1 （Niemann Pick A型和B型）和MCOLN1 （mucolidosis IV型）。有两个具体目标。在Aim1中，我们将确定4个溶酶体的遗传变异，包括GBA， HEXA， SMPD1和MCOLN1。首先，对于初始基因分析，我们将使用来自纽约德系犹太人研究的发现集，包括300例病例和300例对照（NY AJ, NS50487）。我们选择德系犹太人病例和对照作为发现集，因为它是一个基因同质的群体，可能比其他混合群体更强大。其次，我们将使用来自GEPD NS36630和CORE PD NS36630的复制集，其中包括1504例病例和314例对照，将用于检查发现集中发现的变异的等位基因关联。第三，对于在复制集中具有重要意义的等位基因，我们将结合发现集和复制集来估计风险。Aim 2的目标是进一步表征路易体脑尸检样本。首先，我们将在NYBB中可用的其他路易体病例中确定其他突变携带者。其次，我们将测量酶活性（GBA， HEXA, SMPD1）或mRNA水平，以及神经病理学上定义的溶酶体基因突变的路易体病例与无突变的路易体病例和对照组的鞘脂积累。其次，对有无突变的路易体脑尸检样本进行神经病理学评估，包括皮质、SN、海马和小脑a-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.