The Genetic Regulation and Disease Function of the Frontotemporal Dementia Protei

描述（由申请人提供）：额颞叶痴呆蛋白TMEM 106 B的遗传调节和疾病功能额颞叶痴呆（FTD）是早老性痴呆的第二大常见原因，临床特征为语言、行为控制或两者的恶化。没有有效的治疗方法，进行性神经退行性疾病平均在6-7年内导致死亡。FTD由几个神经病理学亚组组成，可能代表不同的基础病理生理学。最大的亚组（约50%的FTD病例）的特征是43 kD HIV TAR DNA结合蛋白（TDP-43）的病理性包涵体，因此称为额颞叶变性伴TDP-43包涵体，或FTLD-TDP。FTLD-TDP可以是散发性的或家族性的，相当大比例的病例（~10%）可归因于颗粒蛋白前体基因（GRN）突变。以常染色体显性遗传方式遗传，GRN突变似乎通过颗粒蛋白原（一种对神经元具有营养作用的分泌蛋白）的单倍不足引起FTLD-TDP。最近，我们在FTLD-TDP中进行了一项全基因组关联研究（GWAS），确定了一个仅含有未表征基因TMEM 106 B的7 p21位点，该位点在非孟德尔和GRN突变相关的FTLD-TDP中均增加了FTLD-TDP的风险。风险相关遗传变异的携带者和患病个体独立地显示TMEM 106 B的mRNA表达增加，强烈暗示该基因是GWAS信号的原因。除了TMEM 106 B是迄今为止描述的FTLD-TDP的非孟德尔病例的唯一风险因素这一事实之外，对其知之甚少。然而，初步数据表明，TMEM 106 B表达在FTLD-TDP中增加，TMEM 106 B受microRNA miR- 132和miR-212调节，这两者在FTLD-TDP中均降低，即TMEM 106 B表达增加导致内体-溶酶体功能障碍，并且TMEM 106 B表达增加导致颗粒蛋白前体运输异常。这些数据导致了一个工作模型，其中TMEM 106 B的遗传变异通过增加TMEM 106 B表达而增加FTLD-TDP的风险。增加的TMEM 106 B表达反过来改变了内体-溶酶体功能，这影响颗粒蛋白前体的正确分选、内化或分泌。该项目的具体目的是测试工作模型，目的1：确认TMEM 106 B过表达与疾病状态和TMEM 106 B风险基因型的关联~目的2：研究TMEM 106 B基因表达调控的精确顺式作用机制~目的3：阐明TMEM 106 B在内体-溶酶体途径以及颗粒蛋白前体运输中的正常和病理生理功能。该提案的主要目标是从GWAS获得的TMEM 106 B和FTLD-TDP之间的统计关联，转向对TMEM 106 B的遗传调控和该蛋白质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景观。

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.