A Role for Drosophila p38 MAP Kinase in Protein Homeostasis. Alysia D. Vrailas-Mortimer^1,2, Amelia M. Burch¹, Subhabrata Sanyal^1,2,3. 1) Cell Biology, Emory University, Atlanta, GA; 2) Center for Behavioral Neuroscience, Atlanta, GA; 3) Center for Neurodegenerative Disease, Emory University, Atlanta, GA.

   One hallmark of aging is the formation of protein aggregates in the brain and musculature, which is often magnified in a disease state such as Alzheimers disease, though the significance of these aggregates or how they contribute to a disease state is not precisely understood. These protein aggregates can be cleared through several mechanisms, such as Chaperone Assisted Selective Autophagy (CASA) a specialized form of autophagy that utilizes a BAG3-HspB8-Hsp70 chaperone complex to target specific protein substrates for degradation through the lysosome. In Drosophila, age-dependent protein aggregation is delayed in long-lived mutant strains suggesting that either preventing protein aggregation or efficient resolution of aggregates plays an important role in aging. We have previously reported that the p38 MAPK (p38K) is a regulator of lifespan and oxidative stress. We have found that inhibition of p38K leads to increased protein aggregation, whereas over-expression of p38K coincides with a reduction in the number of protein aggregates throughout life and is protective against oxidative stress induced aggregation. These data suggest that p38K may play an integral role in general and damage induced protein homeostasis. Furthermore, the Drosophila Protein Interaction Map project has shown that the CASA complex member HspB8 binds to p38K. We therefore hypothesize that p38K may play an integral role in regulating CASA throughout the aging process. We have found that p38K co-localizes with CASA complex members in the muscle and our preliminary data suggests that p38K genetically interacts with select members of the CASA complex to regulate lifespan. To determine if p38K is required for the clearance of CASA specific substrates, we are testing if p38K modifies the phenotypes of protein aggregation disease models such as spinocerebellar ataxia 3 and the Alzheimers disease A model.