TMEM106B in neurodegenerative disease

神经退行性疾病-阿尔茨海默病(AD)、帕金森病(PD)、额颞部 痴呆症(FTD)、肌萎缩侧索硬化症(ALS)和其他--共同构成了最重要的 人类健康中未得到满足的挑战，影响着全世界5000多万人，没有任何治疗方法来减缓或阻止进展。随着2005年全基因组关联研究的到来，以及随后的 识别数百种常见的AD、PD、FTD和ALS的变异危险因素，我们有许多基因座可能 转化为治疗干预的新靶点。然而，到目前为止，很少有机械论的研究是 作为这些GWAS生成的线索的后续行动执行。这一一般规则的一个例外是 关于7p21基因座，我们和其他人在2010年报告了与AD相关的痴呆症FTD的风险。在 在R01的前五年，我们使用了计算和基于基准的方法相结合的方法来确定 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 目的基因TMEM106B的多态(SNPs)和表达。我们进一步定义了因果关系 该基因座的遗传变异及其基于CTCF的改变TMEM106B表达的机制 改变TMEM106B的表达对溶酶体途径的有害影响。我们把这些机械装置结合起来 TMEM106B基因对C9orf72所致FTD遗传修饰作用的实验研究 六核苷酸扩增。因此，通过我们的工作和其他人的工作，该领域获得了 了解7p21的遗传风险被赋予的途径，以及 靶向TMEM106B可能在治疗上是可行的。在这份RO1续期申请中，我们建议 加深对TMEM106B生物学的认识，探讨其在多发性神经退行性变中的作用 疾病，并阐明其在溶酶体功能和细胞健康中的作用。 具体目标1：确定GWAS确定的FTD常见变体的遗传修饰物是否有影响 风险因素TMEM106B跨越了一系列神经退行性疾病。我们会调查的 TMEM106B基因对1300名纵向随访的AD、PD、FTD和ALS患者的影响。我们将决定 TMEM106B在与GBA突变相关的帕金森病中是否起到遗传修饰作用。 特异性目标2：阐明TMEM106B表达变化对溶酶体的影响机制 自噬途径功能与细胞健康。我们将跟进前期工作，证明 TMEM106B可能通过VAMP8-Synaxin17途径影响自噬小体-溶酶体融合。我们会 直接测定离子研究TMEM106B对溶酶体酸化的影响 跨越溶酶体膜的电导和TMEM106B在溶酶体膜组装中的作用 液泡型ATPase。

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.