Pathological signatures of CHCHD10 dysfunction in ADRDs

ADRD 中 CHCHD10 功能障碍的病理学特征

• 批准号: 10664970
• 负责人: David E Kang
• 金额: $ 40.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664970
• 关键词: ALS patients; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyotrophic Lateral Sclerosis; Autopsy; Behavioral; Biochemical; Biological Assay; Brain; Cells; Chinese population; Clinical; Code; Cognitive; Disease; Disease Outcome; Electrophysiology (science); European; Exhibits; Failure; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Genes; Hippocampus; Human; Impairment; Link; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Motor; Motor Neurons; Mus; Mutate; Mutation; Neurons; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Physiology; PrP; Prevalence; Proteasome Inhibition; Proteins; Proteome; Proteomics; Reporter; Role; Slice; Stress; Synapses; Synaptic plasticity; Testing; Tissues; Transfection; Transgenic Mice; Transgenic Organisms; Western Blotting; comorbidity; frontotemporal lobar dementia amyotrophic lateral sclerosis; in vivo; misfolded protein; mitochondrial dysfunction; mouse model; mutant; neuroinflammation; neuropathology; novel; promoter; protein TDP-43; proteostasis; proteotoxicity; response; restoration; sciatic nerve; tau Proteins

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.

项目概要 编码线粒体蛋白的 CHCHD10 基因在家族性和散发性中发生突变 额颞叶痴呆 (FTD)、肌萎缩侧索硬化症 (ALS) 和混合型 FTD-ALS。这 中国人群中 FTD 中 CHCHD10 突变的估计患病率为 7.7% 欧洲血统的 FTD-ALS 患者中为 0.68-2.6%，使 CHCHD10 位居第二 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 线粒体功能障碍。然而，由于只有 1 名患者具有 CHCHD10 突变（ALS 相关 CHCHD10R15L) 并且没有 CHCHD10 突变的 FTD 患者来进行尸检，我们不 了解 CHCHD10 驱动的发病机制的病理特征以及这种特征的程度 特征存在于散发性疾病（即 FTD、FTD-ALS、AD）中。由于错误折叠的蛋白质往往 为了堵塞和抑制蛋白酶体，这种错误折叠和易于聚集的蛋白质经常被 易位至线粒体作为蛋白质稳态的替代途径。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，显示出清晰的病理生理表型。 通过利用小鼠模型和人类死后组织以及分子， 生物化学、组织化学、蛋白质组学、电生理学和行为工具集，这 该提案将检验总体假设，即内源性 CHCHD10 的损失（如 散发性 ADRD）和 FTLD/ALS 相关的 CHCHD10 突变驱动多种病理 线粒体蛋白质稳态和自噬清除受到破坏而产生的特征 蛋白质毒性挑战线粒体，WT CHCHD10 的恢复代表了 减轻蛋白毒性负担和疾病结果的可行策略。目标 1 将定义以下角色： 野生型CHCHD10可减轻体内病理表型。目标 2 将识别并验证 FTLD/ALS 相关 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。