Molecular Genetic Analysis of Lysosomal Storage Disorder Genes in PD

PD溶酶体贮积症基因的分子遗传学分析

• 批准号: 7581690
• 负责人: LORRAINE N CLARK
• 金额: $ 35.07万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2012-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7581690
• 关键词: Age; Alleles; Alzheimer' s Disease; Ashkenazim; Autophagocytosis; Autopsy; Biochemical Pathway; Biochemistry; Brain; Cell physiology; Cerebellum; Cerebral cortex; Clinical; Code; Copy Number Polymorphism; Data Set; Defect; Diagnosis; Disease; Disruption; Evaluation; Functional RNA; Ganglioside Sialidase Deficiency Disease; Gene Mutation; Genes; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; Hex A; Hippocampus (Brain); Impaired cognition; LRRK2 gene; Lead; Lewy Bodies; Lewy Body Disease; Lysosomes; Measures; Messenger RNA; Molecular Genetics; Motor Manifestations; Mutation; Neurologic; Neurons; New York; Nonsense Mutation; Numbers; PINK1 gene; Parkinson Disease; Parkinson' s Dementia; Parkinsonian Disorders; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Population; Predisposition; Public Health; Qualitative Evaluations; Risk Estimate; Risk Factors; Role; Sampling; Sequence Analysis; Series; Sphingolipids; Sphingomyelinase; Structural Genes; Structure; Substantia nigra structure; Susceptibility Gene; System; Universities; Variant; brain tissue; case control; disease phenotype; enzyme activity; follower of religion Jewish; gain of function; genetic analysis; glucosylceramidase; instrument; interest; mind control; mutation carrier; parkin gene/protein; synuclein; trafficking

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.

描述（由申请方提供）：我们假设葡萄糖脑苷脂酶基因和相同生化途径中的其他溶酶体基因（包括氨基己糖苷酶A（HEXA）、鞘磷脂磷酸二酯酶1（SMPD 1）和粘磷脂1（MCOLN 1））突变可能会破坏α-突触核蛋白的细胞加工和运输，并导致路易体形成。在我们之前的研究中，R21，NS 050487，我们已经表明葡萄糖脑苷脂酶基因突变是PD和路易体病的危险因素。在本申请中，我们建议继续我们对GBA基因的研究，并将在临床表征的PD患者和对照以及LBD脑库样本中检查三种额外的溶酶体基因，即引起溶酶体贮积症的突变，即HEXA（Tay Sachs）、SMPD 1（Niemann Pick A型和B型）和MCOLN 1（粘脂沉积症IV型）。有两个具体目标。在Aim 1中，我们将鉴定4种溶酶体的遗传变异，包括GBA，HEXA，SMPD 1和MCOLN 1。首先，对于初始基因分析，我们将使用来自NY Ashkenazi犹太人研究的发现集，包括300例病例和300例对照（NY AJ，NS 50487）。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 NS 36630和CORE PD NS 36630的复制集，其包括1504例病例和314例对照，其将用于检查发现集中鉴定的变体的等位基因关联。第三，对于在复制集中有意义的等位基因，我们将联合收割机结合发现集和复制集来估计风险。目标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提供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，SMPD 1）或mRNA水平，以及与无突变的Lewy小体病例和对照相比，在神经病理学定义的具有溶酶体基因突变的Lewy小体病例中的鞘脂蓄积。其次，具有和不具有突变的路易体脑尸检样品的神经病理学评价将包括皮质、SN、海马和小脑中α-突触核蛋白阳性结构的定量和定性评价。公共卫生相关性：值得注意的是，最近的研究表明，溶酶体基因的突变可能与PD和溶酶体/自噬途径也涉及PD的发病机制。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。