Sunday, April 28, 2024
4/28/2024
Abstract Neuronal function depends on the precise localization and release of neuromodulators, such as growth factors, in response to stimuli. Our lab recently identified an unexpected, but exciting role for ER stress sensor PERK, PKR-like ER kinase, in neuronal growth factor localization. Specifically, in the absence of PERK, a dendritic TGF-ß-like growth factor is mistargeted to the axons, while an axonal insulin-like-growth factor (IGF) is retained in the cell body. Interestingly, PERK is genetically linked to the tauopathies Alzheimer’s Disease (AD) and Progressive Supranuclear Palsy (PSP). At least two of the three genetic variants have decreased kinase activity, but it is unknown how decreased activity is a risk for disease. Impairment of PERK’s role in the correct localization of neuroprotective IGF and TGF-ß-like growth factors could provide a molecular connection to neurodegeneration. Because it is unclear how PERK may directly mediate growth factor localization, I asked whether PERK functions through one of its known downstream targets. Strikingly, I found that CaMKII, a kinase whose function is critical for neural plasticity and memory, is genetically downstream of PERK. Importantly, CaMKII has a known function in axonal targeting of neuropeptides, which has the potential to explain PERK’s novel role in growth factor localization. This proposal aims to define how PERK and CaMKII interact to control axonal-dendritic targeting of select neuroprotective growth factors. To do this, I will test whether PERK acts through its kinase activity, whether phosphorylation-dependent activation state of CaMKII affects growth factor localization, and whether PERK directly phosphorylates CaMKII. The proposed studies will be completed primarily at Drexel University under the guidance of the sponsor and co-sponsor; however, I will seek guidance from my collaborators at UPenn, especially for the advanced in vitro kinase assays to test whether PERK directly phosphorylates CaMKII proposed in Aim 2. Together with my sponsors, I have developed a comprehensive training plan that addresses training in hypothesis-driven research, scientific communication and writing, and career development, as well as augmenting my formal training in neuroscience. The overarching goal of this pre- doctoral fellowship project is to guide me in preparing for an independent career in biomedical research, focusing on the areas related to protein-based pathology in neurodegeneration.
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