Wednesday, April 2, 2025
4/2/2025
The Role of Cyclin C in mediating neurodegenerative proteinopathies - Alzheimer’s disease (AD), Parkinson’s disease (PD), Lewy body disease, amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and prion disease constitute a group of neurogenerative diseases called proteinopathies. They are characterized by the accumulation of aggregated and misfolded proteins in the central nervous system. The identities of the aggregated disease proteins have been identified but how they work at a mechanistic level and contribute to disease pathogenesis remains unclear. Moreover, despite having common co- occurring pathology, little is known about the relationship between these proteinopathies, complicating potential treatment options. Recent evidence has shown a link between the mitochondrial-mediated clearance of aggregated proteins and the preservation of neuronal cell integrity. Likewise, established model systems of proteinopathies have both demonstrated similar results and carved a way to study the molecular details of these diseases. In this grant, we propose to the budding yeast S. cerevisiae and mammalian cells including neurons to address the role of mitochondria and cyclin C in the clearance of the aggregated disease proteins. Of these proteins TDP-43, has emerged as a key player in AD, ALS, and FTLD. Studies in yeast have revealed that cyclin C, a conserved member of the Cdk8 kinase module of the mediator complex, plays a role in TDP-43 toxicity. Our studies point to cyclin C’s known interaction with mitochondria, contributing to TDP-43 mediated-cell death. In this proposal, we will determine the molecular details of the relationship between cyclin C and TDP-43, mitochondria, and cell viability in yeast (Aim 1) and mammalian systems (Aim 2). Together these studies should provide insight into the role cyclin C plays in proteinopathies.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).