The mechanisms that maintain proper function and folding of the proteome (proteostasis) decline during normal aging, which facilitates the onset and progression of neurodegenerative protein misfolding diseases, including Alzheimer's Disease. The functional integrity of the proteome is safeguarded from stress through the combined action of a cohort of transcription factors, each primed to respond to specific forms of proteotoxic stress. During aging, these responses decline and ultimately precipitate a collapse of proteostasis. C. elegans is an excellent model to study the molecular mechanisms involved in this complex process: in particular, the inducibility of the heat shock response, mitochondrial unfolded protein response, ER unfolded protein response, and the oxidative stress response all rapidly decline concurrent with early signs of declining proteostasis. Why the inducibility in response to diverse forms of proteotoxic stress declines, however, is poorly understood, but coincides with the formation of repressive chromatin marks at stress loci. We have identified inappropriate sumoylation during aging as a potential mechanism to explain loss of stress response inducibility. This project will explore how changes in sumoylation during aging alter the epigenome, inducibility of stress responses, and maintenance of proteostasis. The objectives of this proposal are to identify nuclear changes in sumoylation during aging and gain mechanistic insight into how altered sumoylation intersects with changes in chromatin, inducibility of stress response, and the consequence on proteostasis and longevity. Our central hypothesis is that the inducibility of stress response programs maintaining proteostasis declines because increased sumoylation results in aberrant recruitment of chromatin remodeling complexes to stress loci. We have discovered an age-associated increase in sumoylation of a transcriptional regulator of proteostasis, and blocking sumoylation prevents the downregulation of stress response in adult animals. Conversely, preventing deSUMOylation shortens lifespan and represses gene expression. Notably, expression can be rescued by inactivation of chromatin modifying enzymes, consistent with the notion that age-related changes in sumoylation are linked to the activity of chromatin remodeling complexes.
Aim 1 is centered on deciphering whether increasing sumoylation during early C. elegans aging, which coincides with the precipitous drop in stress response, is causative in declining proteostasis and longevity.
Aim 2 centers on a mechanistic analysis to identify interconnections between sumoylation, chromatin remodeling complexes, and changes in chromatin at stress loci. The focus of Aim 3 is on the transcription factors themselves that directly regulate components of the proteostatic network and the functional consequence of their sumoylation during aging. Many of the causative factors of neurodegenerative diseases are sumoylated and mutations in core components of the sumoylation machinery are found in AD patients. Thus, elucidating the intersection between sumoylation, chromatin, and the proteostatic network may have implications for the treatment of neurodegenerative disease and efforts to improve healthy aging.
Our work will establish how sumoylation limits the transcriptional inducibility of components of the proteostatic network that resolve diverse forms of stress. Understanding mechanisms that preserve proteostasis will expedite development of rationale approaches to treat wide-spread protein misfolding diseases, such as Alzheimer's Disease and improve healthy aging.
