Alzheimer’s disease (AD) and other types of tauopathies are proteinopathies. The unfolded protein response (UPR) which is a cellular response to remediate proteinopathy in the endoplasmic reticulum (ER), has been observed in post-mortem brains in several neurodegenerative diseases. Dysregulation of the ER stress response is suggested also by genetic evidence. Single nucleotide polymorphisms (SNP) associated with increased risk for tauopathy were identified by multiple large Genome-Wide Association Studies (GWAS) for PERK (Eukaryotic translation initiation factor 2-alpha kinase 3). PERK acts as one of the sensors and responders for ER stress, regulating a coordinated cellular response to maintain protein quality and to resolve proteostatic stress due to misfolded proteins. The integrity of the UPR when faced with ER stress must be kept intact to maintain the integrity of the proteome. Alterations of these fundamental mechanisms will result in cellular demise and degeneration. Although the tauopathy-related PERK risk variant is found in about 30% of the population, how the SNPs affect the performance of the UPR is not clear. Nor do we yet know if the carriers of the risk SNPs can alter their UPR response through pharmacological interventions. Filling this gap in our understanding of the genetic variation dependent regulation of PERK function will enable us to more effectively target this pathway, improving clinical trial outcomes and clinical management efficacy. In this proposal, we will test the hypothesis that the SNPs enhance PERK activation, exacerbating the neurodegenerative process, and that it can be reversed by blocking the Integrated Stress Response (ISR). The tauopathy related PERK risk variant identified in GWAS is in the same haplotype with three SNPs in the coding region, namely p.S136C, p.R166Q and p.S704A (PERK Haplotype B). We found that the PERK Haplotype B compared to its isogenic control caused gain of function. In this proposal, we will test the hypothesis that the SNPs enhance PERK activation, exacerbating the neurodegenerative process, and that it can be reversed by blocking the Integrated Stress Response (ISR). We have also generated an isogenic mouse model with the PERK risk variant for testing this hypothesis in vivo. We have a team of investigators experienced in the methodologies for studying neurodegeneration and ER stress using the human induced pluripotent stem cell (iPSC) in vitro and mouse in vivo models. We will test our hypothesis in two aims. Aim 1: Determine how the PERK risk SNP variants confer GOF of PERK activity and neurodegeneration. Aim 2: Determine if PERK Haplotype B risk variant accelerates neurodegeneration through overactivation of the ISR in vivo. Our goals are to use the knowledge gained in this application to establish a targeted treatment response dependent on the genotype, for ISR inhibitors and personalized therapy that would be most effective for the patients based on their PERK genotypes.