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Pathological signatures of CHCHD10 dysfunction in ADRDs

ADRD 中 CHCHD10 功能障碍的病理学特征

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目摘要编码线粒体蛋白的CHCHD 10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CHCHD 10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 CHCHD 10 S59 L 突变和ALS CHCHD 10 R15 L突变促进CHCHD 10聚集，线粒体功能障碍然而，由于只有1例CHCHD 10突变（ALS相关）患者， CHCHD 10 R15 L），并且没有携带CHCHD 10突变的FTD患者进行尸检，我们不了解CHCHD 10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）CHCHD 10 WT、CHCHD 10 R15 L或CHCHD 10 S59 L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CHCHD 10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 CHCHD 10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将确定野生型CHCHD 10减轻体内病理表型。目标2将确定和验证 FTLD/ALS连锁CHCHD 10突变的神经病理学特征。目标3将决定突变体CHCHD 10在体内线粒体自噬通量中的作用。