A Bacterial Metabolite Causes Changes in Neurodegeneration and Aging Via Bioactivation and Hormesis in Caenorhabditis Elegans

Abstract

Millions of individuals worldwide are affected by neurodegenerative disorders, that result in the progressive deterioration of cells within the nervous system and particular regions of the brain. A leading risk factor to developing neurodegenerative disorders is aging, however, aging cannot be defined by one specific causative agent. A combination of both genetic and environmental factors contribute to the acceleration of cellular damage. This multi-causal deterioration of cells renders individuals more susceptible to diseases.Parkinson's Disease is classified as an idiopathic disorder, with 90% of cases sporadic in nature. Increasing evidence points towards the environment or a combination of both genetic and environmental insults as contributors to the progression of neuronal death and aging. Developing an appropriate cellular defense response to such insults is important for survival and favorable outcomes. Using the model organism Caenorhabditis elegans, I investigated how exposure to a complex secondary compound produced by the soil bacterium, Streptomyces venezuelae, resulted in a specific transcriptional signature associated with activation of detoxification and stress response programs. Analysis revealed neurodegeneration was enhanced through bioactivation of the secondary compound by Phase I and II enzymes, cyp − 35B2. When animals were exposed to this secondary compound at different concentrations, a hormetic aging response was seen. Underlying both phenotypes was the requirement of the stress activated transcription factor DAF-16. The expression pattern of such genes and the differences in longevity depended on functional DAF-16. Previously identified environmental sources of neurodegeneration and aging are known to target mitochondria. Further aging analysis revealed the hormetic longevity response worked through activation of the AMPK pathway, an important regulator of mitochondrial energy and homeostasis that signals to DAF-16. While other gram-positive bacterial sources of neurodegeneration have been identified, the transcriptional signature here differs. These data illuminate the unique nature of this environmental compound and how it regulates a specific set of genes to influence neurodegeneration and aging and provides further understanding of how environmental contributors impact cellular health and aging pathways. They also indicate the importance of dose when working with environmental factors allowing for the identification of targeted therapy treatments for patients.