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.