Investigating the role of the endoplasmic reticulum unfolded protein response in tauopathy

Project Summary/Abstract Abnormally aggregated tau protein is one of the main neuropathological hallmarks of Alzheimer’s disease (AD), and correlates with disease presentation and severity. The mechanism by which tau causes neurodegeneration is unknown. Abnormal activation of the endoplasmic reticulum unfolded protein response (UPRER) has been implicated in AD and other tauopathies. The proposed project will leverage genetic approaches in C. elegans to identify therapeutically tractable molecular mechanisms in the UPRER that modulate tauopathy. The UPRER also becomes dysfunctional in aging, and tauopathies often coincide with advanced age. Therefore, understanding the aberrant UPRER in the context of tauopathy is crucial for neurodegeneration and aging research. Hypothesis: Abnormal UPRER activation promotes pathological tau accumulation and facilitates synergistic toxicity with TDP-43.The proposed work will address two Specific Aims: 1) Identify UPR-related genes enhancing tauopathy phenotypes by monitoring tau turnover, and 2) Determine the role of UPR activation in TDP-43 cleavage and localization relative to tau. The research and training plan will be conducted in the Kraemer laboratory at the University of Washington with the support of Drs. Brian Kraemer, Nicole Liachko, and Caitlin Latimer. The strong neuroscience, neurology, and C. elegans research communities between the University of Washington, Fred Hutchinson Cancer Research Center, Puget Sound VA, and other institutions will provide resources, scientific expertise, and clinical opportunities that support physician scientist training and enable the successful completion of this proposal.