CHCHD10 in Tauopathy in AD and ADRD

About This Grant

Project Summary Mitochondrial dysfunction is an early event in neurodegenerative diseases including Alzheimer's disease (AD) and Frontotemporal lobar degeneration with tau pathology (FTLD-Tau). Tauopathy is defined by abnormal Tau protein aggregation and hyperphosphorylation, which results in the formation of neurofibrillary tangles within neurons in AD and FTLD-Tau. CHCHD10 plays a crucial role in regulating diverse mitochondrial functions, such as respiration, genome stability, dynamics, cristae organization, and oxidative phosphorylation. In our preliminary study, CHCHD10 was found to be downregulated in the brains of AD, FTLD-Tau, AD-derived neurons, and P301S-Tau mice. Furthermore, either depletion or the presence of CHCHD10-Q95* increases tau seeding activity and tau aggregation in vitro cell lines. Increasing CHCHD10 significantly reduced tau pathology in P301S- Tau mouse brains, human AD fibroblast-converted neurons, and in vitro cell lines. As a result, this study has two major goals: (1) to validate and extend CHCHD10's role in these phenotypes in vivo and ex vivo, and (2) to investigate potential mechanisms by identifying proteomics and transcriptomics signatures in CHCHD10- transduced human neurons derived from AD patients and assess the post-translational modifications on human tau altered by CHCHD10 in PS19 mouse brain. The successful completion of this proposal will: (1) provide insights into CHCHD10-associated mechanisms in tauopathy in AD; and (2) facilitate the therapeutic potential of increasing CHCHD10 in tauopathy in AD.