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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：
10454350
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/10454350
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 (Brain)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 Proteins Proteome Proteomics Reporter Role Slice Stress Synapses Synaptic plasticity Testing Tissues Transgenic Mice Transgenic Organisms Western Blotting burden of illness comorbidity frontotemporal lobar dementia-amyotrophic lateral sclerosis in vivo misfolded protein mitochondrial dysfunction mouse model multicatalytic endopeptidase complex mutant neuroinflammation 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.

项目总结