The impact of rare variants in lysosomal genes in the pathogenesis of Parkinson disease

溶酶体基因罕见变异对帕金森病发病机制的影响

• 批准号: 254694855
• 负责人: Professor Dr. Günther Deuschl
• 金额: --
• 依托单位: Institut für Klinische Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/254694855?language=en
• 关键词: impact; rare; variants; lysosomal; genes

Parkinson disease (PD) is one of the commonest and most serious neurodegenerative disorders. A causative therapy for PD does not exist. PD is a genetically complex disorder in most patients and monogenic in a minority.GWAS studies are limited to a relatively small number of common variants per gene. Recent large exome sequencing projects have demonstrated that the majority of protein coding rare variants have frequencies in the range of 1:1000 to <1:10.000 alleles. The best method to assess the role of rare variants is DNA sequencing. GWAS findings explain only a small part of the estimated heritability of Parkinson disease. Part of the remaining missing heritability will be due to rare variants. The impact of rare variants has already been shown for numerous disorders including Alzheimers disease. However, the impact of rare variants has not been systematically assessed in large patient and control samples due to the high cost of Sanger sequencing. Next-Generation-Sequencing (NGS) now offers a much more economic means to obtain very large amounts of DNA-sequence data.Lysosomes play an extremely important role in the pathogenesis of PD. Alpha-Synuclein (a-syn) is the key pathogenic protein in sporadic PD. Alpha-syn aggregates spontaneously and is a major constituent of the pathognomonic intraneuronal inclusions termed Lewy bodies. Lysosomes degrade soluble and aggregated a-syn using different pathways. Aggregated or otherwise pathologically altered a-syn impairs lysosomal function. Large studies showed that rare heterozygous variants in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA) are strongly associated with Parkinson disease. These mutations interfere with a-syn degradation. Lysosomes are involved in the removal of defective mitochondria and this function is also disturbed in PD. In addition, a number of genes causing monogenic PD are implied in lysosomal function (e.g. LRRK2, VPS35, PINK1, PARK2, ATP13A2).We propose to sequence 18 carefully selected lysosomal candidate genes in 2500 PD patients and the same number of controls. An already tested DNA pooling strategy guarantees a very economic, yet thorough sequence analysis. These data will not only allow us to obtain a detailed view of the role of rare variants in lysosomal genes in PD but will also provide a unique dataset to test and establish novel statistical tools for the analysis or rare variant associations. Since rare variants are more likely to have a large impact on gene function the findings might also enable us to improve biological studies of lysosomal gene malfunction in PD. Kiel University is an ideal location for such a study because the applicants dispose of expertise in Parkinson disease (G. Deuschl), neurogenetics (G. Kuhlenbäumer), NGS (A. Franke) and statistical genetics (M. Krawcak). In addition we have one of the largest NGS facilities in Germany.

帕金森病（Parkinson disease，PD）是最常见、最严重的神经退行性疾病之一。不存在PD的病因治疗。帕金森病是一种遗传复杂的疾病，在大多数患者和少数单基因。GWAS研究仅限于相对较少的常见变异基因。最近的大型外显子组测序项目已经证明，大多数蛋白质编码罕见变体具有在1：1000至<1：10.000等位基因范围内的频率。评估罕见变异作用的最佳方法是DNA测序。GWAS的研究结果只能解释帕金森病估计遗传性的一小部分。剩余的遗传性缺失部分将归因于罕见变异。罕见变异的影响已经在包括阿尔茨海默病在内的许多疾病中得到证实。然而，由于桑格测序的高成本，尚未在大的患者和对照样本中系统地评估罕见变异的影响。下一代测序技术（Next-Generation-Sequencing，NGS）为获得大量DNA序列数据提供了一种更为经济的手段。α-突触核蛋白（α-syn）是散发性PD的关键致病蛋白。α-syn聚集自发，是一个主要组成部分的pathognomonic神经元内包涵体称为路易体。溶酶体使用不同的途径降解可溶性和聚集的α-syn。聚集或以其他方式病理改变的α-syn损害溶酶体功能。大量研究表明，编码溶酶体酶葡萄糖脑苷脂酶（GBA）的基因中的罕见杂合变体与帕金森病密切相关。这些突变干扰α-syn降解。溶酶体参与去除有缺陷的线粒体，并且该功能在PD中也受到干扰。此外，许多导致单基因PD的基因（如LRRK 2、VPS 35、PINK 1、PARK 2、ATP 13 A2）都与溶酶体功能有关，我们建议对2500例PD患者和相同数量的对照组中18个溶酶体候选基因进行测序。 一个已经测试过的DNA池策略保证了一个非常经济，但彻底的序列分析。这些数据不仅使我们能够详细了解溶酶体基因中罕见变异在PD中的作用，还将提供一个独特的数据集，以测试和建立用于分析罕见变异相关性的新统计工具。由于罕见变异更可能对基因功能产生重大影响，因此这些发现也可能使我们能够改善PD中溶酶体基因功能障碍的生物学研究。基尔大学是一个理想的地点，这样的研究，因为申请人处置的专业知识在帕金森病（G。Deuschl）、神经遗传学（G. Kuhlenbäumer），NGS（A. Franke）和统计遗传学（M. Krawcak）。此外，我们还拥有德国最大的NGS工厂之一。