Pathological signatures of CHCHD10 dysfunction in ADRDs

项目摘要 编码线粒体蛋白的CHCHD10基因在家族性和散发性中突变， 额颞叶痴呆（FTD）、肌萎缩侧索硬化症（ALS）和混合型FTD-ALS。的 中国人群中FTD中CHCHD10突变的估计患病率为7.7%， 在欧洲血统的FTD-ALS患者中为0.68 - 2.6%，使CHCHD 10成为第二大 FTD和FTD-ALS中的常见突变基因。我们知道FTD-ALS CHCHD10S59L 突变和ALS CHCHD10R15L突变促进CHCHD10聚集， 线粒体功能障碍然而，由于只有1例CHCHD10突变（ALS相关）患者， CHCHD10R15L），并且没有携带CHCHD10突变的FTD患者进行尸检，我们不 了解CHCHD10驱动的发病机制的病理特征，以及在多大程度上 在散发性疾病（即FTD、FTD-ALS、AD）中存在特征。由于错误折叠的蛋白质 为了阻塞和抑制蛋白酶体，这种错误折叠和易于聚集的蛋白质经常被 转移到线粒体中作为蛋白质稳定的替代途径。我们最近生成了 表达野生型（WT）CHCHD10WT、CHCHD10R15L或CHCHD10S59L的转基因（Tg）小鼠 由神经元小鼠PrP启动子驱动，显示出明确的病理生理表型。 利用小鼠模型和人死后组织， 生物化学、组织化学、蛋白质组学、电生理学和行为学工具集， 该提案将检验总体假设，即内源性CHCHD 10的丧失（如 散发性ADRD）和FTLD/ALS连锁CHCHD10突变驱动不同的病理性 线粒体蛋白质稳态和自噬清除的破坏导致的特征 蛋白质毒性挑战的线粒体，WT CHCHD10的恢复代表了一个新的挑战。 减轻蛋白毒性负担和疾病结果的可行策略。目标1将确定 野生型CHCHD10减轻体内病理表型。目标2将确定和验证 FTLD/ALS连锁CHCHD10突变的神经病理学特征。目标3将决定 突变体CHCHD10在体内线粒体自噬通量中的作用。

Project Summary The CHCHD10 gene coding for a mitochondrial protein is mutated in familial and sporadic Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and mixed FTD-ALS. The estimated prevalence of CHCHD10 mutations is 7.7% among FTD in the Chinese population and 0.68-2.6% among FTD-ALS patients of European descent, making CHCHD10 the second most frequently mutated gene in FTD and FTD-ALS. We know that the FTD-ALS CHCHD10S59L mutation and the ALS CHCHD10R15L mutation promotes CHCHD10 aggregation and mitochondrial dysfunction. However, as only 1 patient with CHCHD10 mutation (ALS-linked CHCHD10R15L) and no FTD patient with CHCHD10 mutation has come to autopsy, we do not know the pathological signatures of CHCHD10-driven pathogenesis and to what extent such signatures are present in sporadic diseases (i.e. FTD, FTD-ALS, AD). As misfolded proteins tend to clog and inhibit the proteasome, such misfolded and aggregation-prone proteins are frequently translocated into mitochondria as an alternative pathway for proteostasis. We recently generated transgenic (Tg) mice expressing wild type (WT) CHCHD10WT, CHCHD10R15L, or CHCHD10S59L driven by the neuronal mouse PrP promoter, which show clear pathophysiological phenotypes. By taking advantage of mouse models and human postmortem tissues together with molecular, biochemical, histochemical, proteomics, electrophysiological, and behavioral toolsets, this proposal will test the overarching hypothesis that the loss of endogenous CHCHD10 (as seen in sporadic ADRDs) and FTLD/ALS-linked CHCHD10 mutations drive diverse pathological signatures resulting from disruptions in mitochondrial proteostasis and autophagic clearance of proteotoxically challenged mitochondria, and that restoration of WT CHCHD10 represents a viable strategy to mitigate proteotoxic burden and disease outcomes. Aim 1 will define the role of wild type CHCHD10 in mitigating pathological phenotypes in vivo. Aim 2 will identify and validate the neuropathological signatures of FTLD/ALS-linked CHCHD10 mutations. Aim 3 will determine the role of mutant CHCHD10 in mitophagy flux in vivo.