Many late-onset neurodegenerative diseases, such as Huntington's disease (HD), Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS), are caused by the misfolding and aggregation of proteins. The ultimate risk factor for these diseases is aging. Also, in these diseases aggregate-prone proteins affect neurons, which increasingly lose function as the disease advances with age. Individuals stricken with these diseases succumb to the detrimental symptoms associated with them, such as dementia and loss of motor function and ultimately death. Currently, there are no cures for these diseases, and only few treatments to reduce the underlying symptoms are available. Ultimately, the production of more innovative therapeutic approaches will be most important for treatment, and hopefully cure, and understanding of the cellular and genetic pathways involved with protection against protein aggregation will help. In neurodegenerative diseases the aggregation-prone proteins are expressed at birth, although symptoms of disease are not present until later in life. Also, there exists great variability in age of onset among individuals who have the same genetically mutated protein. This suggests the presence of juvenile programs that can protect some resistant individuals later in life. Researchers have been studying known protective pathways that avoid or delay the failure of protein homeostasis (proteostasis) and thus delay or deduce toxic effects of protein aggregation. These approaches have found many ways to improve proteostasis, although often at the risk for delaying development and reproduction. Therefore, the goal of this research is to identify the pathways that act during juvenile stages to protect against protein aggregation and are compatible with normal development, growth, and cellular signaling later in life. This will be accomplished by addressing the following questions: does transient passage through stress-resistant dauer stage protect against protein aggregation, and from phenotypes associated with proteotoxicity later in life? And ultimately, our goal is to identify the mechanisms that are protective during aging when activated in juveniles. Caenorhabditis elegans has a physiological protective program (dauer diapause) that is known to be stress-resistant and protected from aging. The above questions will be addressed by transiently activating dauer program early in life, subsequently allowing for normal development, and observing the effects of these treatments on protein aggregation and toxicity during aging.
The aim of this research is to test whether protective physiological programs that can be activated during development and early in lifespan can improve resistance to protein misfolding and aggregation during aging. Protein misfolding and aggregation contribute significantly to many human diseases, including late-onset neurodegenerative diseases, and is thought to play a significant role in cellular dysfunction in aged organisms. Discovering the cellular and genetic pathways that are protective against protein aggregation in model organisms will improve our understanding of potential treatments for aging-related disease in humans.
