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发生突变 额颞性痴呆(FTD)、肌萎缩侧索硬化症(ALS)和混合性FTD-ALS。这个 在中国人群中，CHCHD10突变的估计患病率为7.7%。 在欧洲血统的FTD-ALS患者中，0.68-2.6%，使CHCHD10成为第二大 FTD和FTD-ALS中频繁突变的基因。我们知道FTD-ALS CHCHD10S59L 突变和ALS CHCHD10R15L突变促进CHCHD10聚集和 线粒体功能障碍。然而，由于只有1名CHCHD10突变患者(ALS相关 CHCHD10R15L)，并且没有携带CHCHD10突变的FTD患者进行尸检，我们没有 了解CHCHD10驱动的致病机制的病理特征及其程度 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倾向于 为了堵塞和抑制蛋白酶体，这种错误折叠和容易聚集的蛋白质经常 转位到线粒体中，作为蛋白质平衡的替代途径。我们最近生成了 表达野生型(WT)CHCHD10WT、CHCHD10R15L或CHCHD10S59L的转基因(TG)小鼠 由神经性小鼠PrP启动子驱动，表现出明确的病理生理表型。 通过利用小鼠模型和人类死后组织以及分子， 生化、组织化学、蛋白质组学、电生理和行为工具集，这 该提案将检验内源性CHCHD10的丧失(见 散发性ADRD)和FTLD/ALS相关的CHCHD10突变导致多种病理改变 线粒体蛋白平衡和自噬清除中断所致的特征 蛋白质毒性挑战线粒体，WT CHCHD10修复代表着一种 减轻蛋白毒性负担和疾病后果的可行战略。目标1将定义 野生型CHCHD10在体内减轻病理表型的作用目标2将识别和验证 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在体内吞噬有丝分裂通量中的作用

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.