The Genetic Regulation and Disease Function of the Frontotemporal Dementia Protei

描述(由申请人提供)：额颞性痴呆蛋白TMEM106B的遗传调节和疾病功能(FTD)是老前期痴呆的第二大常见原因，临床特征是语言和/或行为控制能力下降。没有有效的治疗方法，进行性神经变性平均在6-7年内导致死亡。FTD由几个神经病理亚型组成，可能代表不同的潜在病理生理学。最大的亚群(约占FTD病例的50%)是以43kD的HIV TAR DNA结合蛋白(TDP-43)的病理包涵体为特征的，因此被称为TDP-43包涵体的额颞叶变性，或FTLD-TDP。FTLD-TDP可以是散发性的，也可以是家族性的，相当大比例(~10%)的病例可归因于原颗粒基因(GRN)的突变。以常染色体显性方式遗传的GRN突变似乎通过原颗粒蛋白单倍性不足而导致FTLD-TDP，原颗粒蛋白是一种对神经元具有营养作用的分泌蛋白。最近，我们在FTLD-TDP中进行了一项全基因组关联研究，发现了一个只包含未鉴定基因TMEM106B的7p21基因座，该基因在非孟德尔突变和GRN突变相关的FTLD-TDP中都增加了FTLD-TDP的风险。风险相关基因变异携带者和患病个体单独显示TMEM106B的mRNA表达增加，强烈暗示该基因是Gwas信号的原因。除了TMEM106B是迄今为止所描述的非孟德尔FTLD-TDP病例的唯一危险因素外，人们对此知之甚少。然而，初步数据表明，TMEM106B在FTLD-TDP中的表达增加，TMEM106B的表达受到微RNA miR-132和miR-212的调控，这两种微RNA在FTLD-TDP中都被下调，TMEM106B的表达增加导致内体溶酶体功能障碍，TMEM106B的表达增加导致颗粒蛋白原运输的异常。这些数据导致了一个工作模型，在该模型中，TMEM106B的遗传变异通过增加TMEM106B的表达而增加了FTLD-TDP的风险。TMEM106B表达增加，进而改变内体-溶酶体功能，从而影响原颗粒的正确分选、内化或分泌。该项目将测试工作模型，其具体目的是：目的1：确认TMEM106B过度表达与疾病状态和TMEM106B风险基因型的关系~目的2：研究TMEM106B基因表达调控的确切顺式作用机制(S)~目的3：阐明TMEM106B在内体-溶酶体途径以及颗粒前体运输中的正常和病理生理功能。这项建议的总体目标是从GWAS获得的TMEM106B和FTLD-TDP之间的统计关联，转移到对TMEM106B的遗传调节以及该蛋白的正常和病理生理功能的机械理解。在这个过程中，我们将确定许多潜在的治疗途径，而不是在这种目前无法治愈的疾病的研究和药物发现努力的版图中。

DESCRIPTION (provided by applicant): The Genetic Regulation and Disease Function of the Frontotemporal Dementia Protein TMEM106B Frontotemporal dementia (FTD) is the second-most common cause of presenile dementia, characterized clinically by deterioration in language, behavioral control, or both. There are no effective treatments, and progressive neurodegeneration causes death within an average of 6-7 years. FTD is comprised of several neuropathological subgroups, likely representing different underlying pathophysiologies. The largest subgroup (~50% of FTD cases) is characterized by pathological inclusions of the HIV TAR DNA-binding protein of 43 kD (TDP-43) and accordingly named frontotemporal lobar degeneration with TDP-43 inclusions, or FTLD-TDP. FTLD-TDP can be either sporadic or familial, with a substantial proportion of cases (~10%) attributable to mutations in the progranulin gene (GRN). Inherited in an autosomal dominant manner, GRN mutations appear to cause FTLD-TDP through haploinsufficiency of progranulin, a secreted protein with trophic effects on neurons. Recently, we performed a genomewide association study (GWAS) in FTLD-TDP, identifying a 7p21 locus containing only the uncharacterized gene TMEM106B that confers increased risk of FTLD-TDP in both non-Mendelian and GRN mutation-associated FTLD-TDP. Carriers of risk-associated genetic variants and diseased individuals independently showed increased mRNA expression of TMEM106B, strongly implicating this gene as the cause of the GWAS signal. Beyond the fact that TMEM106B is the only risk factor for non- Mendelian cases of FTLD-TDP described to date, little is known about it. Preliminary data suggest, however, that TMEM106B expression is increased in FTLD-TDP~ that TMEM106B is regulated by the microRNAs miR- 132 and miR-212, which are both decreased in FTLD-TDP~ that increased TMEM106B expression leads to endosomal-lysosomal dysfunction~ and that increased TMEM106B expression leads to abnormalities in progranulin trafficking. These data lead to a working model in which genetic variants at TMEM106B confer increased risk of FTLD-TDP by increasing TMEM106B expression. Increased TMEM106B expression, in turn, alters endosomal-lysosomal function, which influences the proper sorting, internalization, or secretion of progranulin. The Specific Aims of the project, which will test the working model, are: AIM 1: Confirm the association of TMEM106B over-expression with disease states and with TMEM106B risk genotypes~ AIM 2: Investigate the precise cis-acting mechanism(s) by which TMEM106B gene expression is regulated~ AIM 3: Elucidate the normal and pathophysiological function of TMEM106B in endosomal-lysosomal pathways as well as in progranulin trafficking. The over-arching goal of this proposal is to move from a statistical association obtained by GWAS between TMEM106B and FTLD-TDP, to a mechanistic understanding of both the genetic regulation of TMEM106B and the normal and pathophysiological function of this protein. In the process, we will identify many potential avenues for therapy not otherwise in the landscape of research and drug discovery efforts for this currently untreatable disease.