PERK determines polarized targeting of growth factors in neurons

Abstract: This competitive revision will extend the original grant "PERK determines polarized targeting of growth factors in neurons" (1R21AG063029), to explore how human genetic variants in Alzheimer's disease-linked genes, including PERK, affect neuronal sensitivity to SARS-CoV-2 infection. A significant number of AD/tauopathy genes either contribute to the secretory function of cells (when wild type), or disrupt it and cause ER stress and translational silencing (when mutated or damaged). On the other hand, coronaviruses subvert the host cell ER and translational machinery to produce their own proteins. Thus, AD alleles that impact these pathways are hypothesized here to also impact replication of the novel SARS-CoV-2 and the progression of COVID-19. Genetic variants that fit this hypothesis will be identified (Aim 1) by relating the exomes of COVID-19 patients at Geisinger's Health Center to their longitudinal neurological presentation. Because PERK represents one such gene that is already known to both be required for SARS coronavirus infection and to harbor hypomorphic alleles that are a validated risk factor for AD/tauopathy, we will measure (Aim 2) the dependence of SARS- CoV-2 Spike and 3a proteins biosynthesis, and the survival of neurons expressing them, on AD/tauopathy variants in the PERK kinase pathway. Variants such as hypomorphic PERK alleles will be one likely mechanistic explanation for the wide variation in sensitivity to COVID-19. Future work will validate, by cellular and molecular approaches, other AD genes identified in Aim 1 as affecting COVID-19. In addition to testing the genetic connection of AD/tauopathy alleles to altered risk for COVID-19 and neurological complications, our studies will test small molecule drugs that can affect virus production and are also candidates for treatment of neurodegeneration.