Pathological signatures and pathways of CHCHD2 dysfunction in Lewy body diseases

Project Summary / Abstract Accumulation of misfolded α-Synuclein (αSyn) and associated dysfunctions in mitochondrial quality control and lysosomal clearance are cardinal features of Lewy body diseases (LBDs). The CHCHD2 gene coding for a mitochondrial protein is genetically associated with autosomal dominant familial Parkinson’s disease (PD) and other LBDs, with >20 CHCHD2 mutations implicated to date. Our preliminary studies show that CHCHD2 levels decline in sporadic LBDs and that CHCHD2 plays a critical role in brain proteostasis. However, as only 1 patient with a PD-linked CHCHD2 mutation has come to autopsy, we do not know the pathological signatures of CHCHD2-driven pathogenesis, nor do we know to what extent such pathological signatures are present in sporadic LBDs. We recently generated the first transgenic mice expressing wild type CHCHD2 (CHCHD2WT) or PD-linked CHCHD2T61I driven by the neuronal mouse PrP promoter, the latter which captures many pathophysiological phenotypes seen in LBDs. In this proposal, we will test the overarching hypothesis that the PD-linked CHCHD2T61I mutation and the depletion of endogenous CHCHD2 (as in sporadic PD/LBDs) drive diverse pathologies by disrupting proteostasis in the mitochondria-lysosome axis, and that CHCHD2WT restoration mitigates proteotoxic burden and disease outcomes. In aim 1, we will define the role of CHCHD2 in modifying pathological signatures and phenotypes in vivo. In aim 2, we will validate CHCHD2-driven pathological signatures in the mitochondria-lysosome axis. Hence, through leveraging mouse models of LBDs and unbiased methods, this study will identify and validate CHCHD2-related dysfunctions in the brain at mechanistic, transcriptional, and pathological levels, particularly in the mitochondria-lysosome axis. By extending these findings to humans, this proposal is expected to identify novel pathological signatures of human LBDs, which may reveal important new insights to their pathogenesis beyond αSyn.