The Role of Cyclin C in mediating neurodegenerative proteinopathies

This research focuses on a newly implicated protein, cyclin C, and its possible role in neurodegenerative proteinopathies characterized by TDP-43 pathology. Progressive neurological diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis share a hallmark pathology: the aberrant accumulation of misfolded proteins, including TDP-43, in the cytoplasm of neurons. While the presence of protein aggregates has long been associated with neuronal dysfunction and death, the molecular pathways that drive aggregate formation and execute cell death remain incompletely understood. The work focuses on understanding how cyclin C, a conserved protein typically localized to the nucleus, responds to cellular stress by relocating to the cytoplasm and contributing to mitochondrial fragmentation.

Preliminary studies indicate that this stress-induced cytoplasmic relocalization of cyclin C promotes mitochondrial breakup, a process that may accelerate neuronal death in diseases where pathogenic TDP-43 accumulates. Supported by a two-year, $424,450 grant from the National Institute on Aging, Cooper's project seeks to illuminate the mechanistic link between cyclin C behavior and neuron loss in TDP-43-associated disorders. The research addresses critical questions: how and why neurons die in response to pathogenic protein aggregation, whether cyclin C's cytoplasmic activity is causally involved in mitochondrial dysfunction and cell death, and whether cyclin C represents a previously unrecognized contributor to TDP-43 biology.

The discovery of cyclin C as a 'new player' in TDP-43-related disease challenges assumptions that the relevant protein set was already fully known, suggesting that additional, uncharacterized proteins may influence neurodegenerative pathways. The study's significance extends beyond mechanistic insights: by clarifying cyclin C's role in mitochondrial dynamics and cell death, the work could identify new molecular targets for therapies aimed at slowing or preventing neuronal loss. Given demographic trends cited by the World Health Organization, specifically, the anticipated doubling of the population over age 65 in the coming decades, understanding and countering the molecular drivers of neurodegenerative disease is of growing public health importance. In the long term, Cooper hopes her findings will spur further research into other proteins that affect neurodegeneration and ultimately contribute to the development of drugs to cure or slow progression of these currently incurable diseases. The funded study thus represents an effort to connect basic cell biology of cyclin C and mitochondria with the broader goal of revealing therapeutic avenues for TDP-43-associated neurodegenerative disorders.