Cellular and molecular mechanisms of PERK-dependent olfactory defects in neurodegeneration - In most familial neurodegenerative diseases (NDs), specific subsets of neurons are affected despite broad expression of disease-causing mutant proteins. The cause of this selective susceptibility is unknown. Interestingly, olfactory dysfunction long precedes clinical symptoms in many of these diseases. The commonality and early onset of olfactory dysfunction across NDs suggest that olfactory neurons are especially susceptible to neurodegeneration. The molecular mechanisms underlying this susceptibility may indicate shared initiating mechanisms. We found that PERK, a known risk factor for progressive supranuclear palsy and Alzheimer’s disease, is necessary for olfactory function in Drosophila. The disease risk alleles of PERK are hypomorphic, therefore I hypothesize that decreased PERK activity enhances the olfactory system’s susceptibility to neurodegeneration. PERK’s function in the olfactory system may therefore provide new targets for earlier and more effective treatment of neurodegenerative diseases. Because PERK may contribute to olfaction through multiple cellular and molecular functions, this project will determine where and when PERK is needed in the olfactory system, and through which molecular pathways. PERK’s canonical function is to respond to ER stress by phosphorylating eIF2α, thereby attenuating translation. However, PERK has additional, novel roles in axon guidance, Ca2+ dynamics, and growth factor sorting. These functions may affect different populations of neurons and operate within different timeframes. To develop therapies that target PERK-dependent mechanisms driving neurodegeneration without undesirable side effects, it is critical to resolve which of these functions is necessary for olfaction. I will use the extensive genetic tools available in Drosophila to probe for selective PERK dependence among olfactory system neurons of different functional types (e.g., sensory vs. interneuron) and belonging to circuits mapped to different odors. Likewise, to determine whether PERK is necessary in the development, function, or aging of olfactory neurons, I will temporally control PERK expression and activity and assess olfactory function at multiple life stages. Finally, I will determine whether ER stress, eIF2α phosphorylation, or another pathway downstream of PERK is necessary or sufficient to explain the olfactory system’s dependence on PERK. This work will elucidate how PERK modulates early ND symptoms, providing new possible routes towards effective treatment of neurodegeneration and deepening our knowledge of PERK’s broader neuronal functions. Through the duration of this fellowship, I will be guided by a strong team of mentors and collaborators to develop expertise in methods critical to neuroscience research, including optogenetics, fixed and live imaging, and molecular techniques. Likewise, I will gain conceptual knowledge in organization of neural circuits, signaling and stress response pathways, and the neurophysiology of olfaction. This will prepare me for a career of independent research to uncover mechanisms of neural function and disease.
