CHCHD10 Frontotemporal Dementia, Molecular Mechanisms and Therapeutic Strategies

Coiled-helix-coiled-helix domain containing protein 10 (CHCHD10, D10) is the first mitochondrial protein to be associated with familial frontotemporal dementia and amyotrophic lateral sclerosis (ALS). The normal function of D10 remains unknown, but to date several pathogenic D10 mutations have been reported. Our most recent

studies have demonstrated that mutant D10 forms fibrillar amyloid aggregates that could participate in the pathogenesis of D10 frontotemporal dementia and may even contribute to Alzheimer’s disease. We propose that accumulation of mutant D10 amyloid aggregates disrupt mitochondrial proteostasis and activate

mitochondrial integrated stress response (mtISR), leading to widespread metabolic alterations in affected tissues. Gaps in knowledge remain on how D10 mutations affect protein structure, folding, and interactions with mitochondrial membranes, leading to protein aggregation, amyloid formation, mitochondrial dysfunction, and

neuronal degeneration in frontotemporal dementia. The first aim of this MPI R01 application proposes to elucidate the structural and molecular basis of D10 aggregation using an array of state-of-the art biochemical and structural approaches. It will investigate whether D10 fibrils occur in the brain of mouse models and human

postmortem samples and whether their atomic resolution structures differ from those of D10 fibrils formed in vitro. We propose to test whether D10 disease mutants are associated with distinct structural strains, and if D10 fibrils can lead to seeding and spreading of aggregation in cells and in vivo, as in other forms of dementia

associated with amyloid. The second aim is translational in nature and exploits the lack of detrimental consequences of downregulating D10 in vivo. In collaboration with Ionis Pharmaceuticals, it will test the neuroprotective and systemic effects of antisense oligonucleotides against D10 in an animal model of mutant

D10 neurodegeneration, the D10 S55L knock in (KI) mouse. The goal is to decrease the protein aggregation burden and alleviate mtISR and pathology in this mouse model of D10 pathology. The third aim will investigate autophagy in vivo to assess whether it is altered in D10 S55L KI mouse and test approaches to enhance

autophagy in the CNS to eliminate D10 aggregates. Moreover, since general autophagy can eliminate both cytosolic aggregates and mitochondria, to discriminate between these two components, we will use a genetic approach to selectively enhance mitophagy. The proposed project takes advantage of the complementary

expertise of Dr. Kawamata, an expert in modeling and studying neurodegenerative diseases and Dr. Eliezer, an expert in protein structure and biochemistry and in alterations of protein folding and aggregation in neurodegeneration. Successful outcomes of this project could pave the way to clinical development of

therapeutic strategies for D10-linked frontotemporal dementia.