TMEM106B in neurodegenerative disease

神经退行性疾病-阿尔茨海默氏病（AD）、帕金森氏病（PD）、额颞叶神经退行性疾病、阿尔茨海默氏病（AD）、帕金森氏病（PD）、额颞叶神经退行性疾病。 痴呆症（FTD），肌萎缩侧索硬化症（ALS）和其他-一起构成了一个最重要的 人类健康面临的挑战尚未得到解决，影响到全球超过5000万人，没有任何治疗方法来减缓或阻止疾病进展。随着2005年全基因组关联研究（GWAS）的出现，以及随后的 通过对AD、PD、FTD和ALS的数百种常见变异风险因素的鉴定，我们发现许多基因座可能 转化为治疗干预的新目标。然而，迄今为止，很少有机制研究被 作为对这些GWAS生成的线索的随访。这一一般规则的一个例外是， 关于我们和其他人在2010年报告的7 p21基因座，它赋予AD相关痴呆FTD的风险。在 在R 01的前五年，我们使用了计算和基于实验室的方法相结合， 建立GWAS鉴定的单核苷酸之间的表达数量性状基因座（eQTL）关系 多态性（SNP）和靶基因TMEM 106 B的表达。我们进一步定义了因果关系 该基因座的遗传变异，其基于CTCF的改变TMEM 106 B表达的机制，以及 对改变TMEM 106 B表达的溶酶体途径的有害作用。我们把这些机械的 研究FTD中TMEM 106 B基因型对C9 orf 72的遗传修饰作用的实验 六核苷酸扩增。因此，通过我们的工作和其他人的工作，该领域已经获得了 了解7 p21基因的遗传风险是通过什么途径产生的，以及 TMEM 106 B的靶向在治疗上是可行的。在本申请中，我们建议 加深我们对TMEM 106 B生物学的理解，研究其在多种神经退行性疾病中的影响， 疾病，并阐明其在溶酶体功能和细胞健康中的作用。 具体目的1：确定GWAS鉴别的FTD常见变体的遗传修饰作用 危险因素TMEM 106 B延伸到神经变性疾病的范围。我们将调查 TMEM 106 B基因型在>1300例随访的AD、PD、FTD和ALS患者中的作用我们将确定 TMEM 106 B是否在与GBA突变相关的PD中充当遗传修饰剂。 具体目标2：阐明TMEM 106 B表达变化影响溶酶体功能的机制。 自噬通路功能和细胞健康。我们将继续开展初步工作， TMEM 106 B可能通过VAMP 8-Syntaxin 17途径影响自噬体-溶酶体融合。我们将 通过直接测量离子研究TMEM 106 B诱导溶酶体酸化变化 跨溶酶体膜的电导和TMEM 106 B在溶酶体膜组装中的作用的研究。 液泡ATP酶

The neurodegenerative diseases – Alzheimer’s Disease (AD), Parkinson’s Disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and others – together constitute one of the most significant unmet challenges in human health, affecting greater than 50 million people worldwide with no treatments to slow or stop progression. With the advent of the genomewide association study (GWAS) in 2005, and the subsequent identification of hundreds of common variant risk factors for AD, PD, FTD, and ALS, we have many loci that may translate into new targets for therapeutic intervention. To date, however, few mechanistic studies have been performed as follow-up to these GWAS-generated leads. One exception to this general rule has been with respect to the 7p21 locus we and others reported in 2010 to confer risk for the AD-related dementia FTD. In the first five years of this R01, we used a combination of computational and bench-based approaches to definitively establish the expression quantitative trait locus (eQTL) relationship between GWAS-identified single nucleotide polymorphisms (SNPs) and expression of the target gene TMEM106B. We furthermore defined the causal genetic variant at this locus, its CTCF-based mechanism for altering expression of TMEM106B, and the deleterious effects on lysosomal pathways of altering TMEM106B expression. We coupled these mechanistic experiments with investigations of the genetic modifier effects of TMEM106B genotype in FTD due to C9orf72 hexanucleotide expansions. Thus, through our work and the work of others, the field has gained an understanding of the pathways through which genetic risk at 7p21 is conferred, and the groups of patients in which targeting of TMEM106B may be viable therapeutically. In this RO1 renewal application, we propose to deepen our understanding of TMEM106B biology, investigating its influence in multiple neurodegenerative diseases, and elucidating its role in lysosomal function and cellular health. Specific Aim 1: Determine whether genetic modifier effects of the GWAS-identified FTD common variant risk factor TMEM106B extend across a spectrum of neurodegenerative diseases. We will investigate TMEM106B genotype effects in >1300 longitudinally-followed AD, PD, FTD, and ALS patients. We will determine whether TMEM106B acts as a genetic modifier in PD associated with GBA mutations. Specific Aim 2: Elucidate the mechanisms by which changes in TMEM106B expression affect lysosomal- autophagy pathway function and cellular health. We will follow-up preliminary work demonstrating that TMEM106B may affect autophagosome-lysosome fusion through a VAMP8-Syntaxin17 pathway. We will investigate TMEM106B-induced changes in lysosomal acidification through direct measurement of ion conductances across the lysosomal membrane and investigations of TMEM106B’s role in assembly of the vacuolar ATPase.