Tauopathies are devastating neurodegenerative diseases that impair cognition, memory, movement, strength, and vision. Tauopathies are caused by the accumulation of misfolded pathologic tau protein in affected brain regions. Tauopathies like Alzheimer's Disease affect millions of aging Veterans. Tauopathies also affect younger Veterans who develop Chronic Traumatic Encephalopathy after repeated blast exposure head trauma. The Veterans Health Administration expends significant resources supporting tauopathy patients, but, there are no cures. These diseases are all fatal. Therefore, there is a critical need to identify ways to treat these patients and to prevent functional debilitation arising from tauopathy neurodegenerations. In this VA Merit award, we investigated a recently discovered genetic risk factor for tauopathies: EIF2AK3/PERK. EIF2AK3/PERK encodes a protein kinase that prevents protein misfolding in cells. We found that patient stem cell-derived neurons carrying EIF2AK3/PERK tauopathy variants showed reduced kinase activity, increased tau pathology, and increased vulnerability to stress-induced cell death. Last, we found that small molecule activation of EIF2AK3/PERK signaling reduced tau protein pathology in vitro. Based on our findings, we hypothesize that EIF2AK3/PERK determines tauopathy neurodegeneration risk in people by regulating tau protein pathology and neuronal vulnerability to ER stress. Furthermore, our data reveal an exciting, new strategy to treat tauopathy by pharmacologically enhancing EIF2AK3/PERK signaling. To advance and translate our findings from the prior funding period, in our renewal application, we propose preclinical studies to evaluate neurologic function outcomes after genetic or pharmacologic enhancement of EIF2AK3/PERK signaling in mouse models of tauopathy neurodegeneration. Our 3 specific aims for the renewal application are: Specific Aim 1. Test how genetic enhancement of EIF2AK3/PERK affects disease onset, progression, and survival in preclinical mouse model of tauopathy neurodegeneration. Specific Aim 2. Evaluate therapeutic potential of orally bioavailable phosphatase inhibitors in tauopathy mice. Specific Aim 3. Characterize proteostatic properties of new small molecule activators of EIF2AK3/PERK pathway. In the animal studies, we will employ the PS19 tauopathy mouse model that expresses human misfolded tau in the mouse nervous system and develops phenotypes similar to human tauopathy diseases. We will perform batteries of behavioral tests to measure neurologic function with respect to cognition, memory, locomotion, strength, and vision after genetic or pharmacologic treatments. We will also track animal survival after genetic or pharmacologic modulation of EIF2AK3/PERK pathway. In the drug screening studies, we will quantify tau protein aggregation in dose-response studies after small molecule treatment using biochemical and cellular assays to identify new “top hit” compounds that reduce tau patholo...