Analysis of Nrf1 pathway in Alzheimer's Disease

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and memory loss. One of the defining pathological hallmarks of AD at the molecular level is the presence of neurofibrillary tangles composed of aggregates of hyperphosphorylated tau in the neurons. These aggregates impose a severe burden on the neuronal protein quality control pathways resulting in severe proteotoxic stress in these cells. Sustained proteotoxic stress typically results in neuronal cell death culminating in brain atrophy, a prominent pathological feature of AD. Our previous work has firmly established the transcription factor Nrf1 as a central player in responding to cellular proteotoxic stress. Nrf1, by its ability to induce de novo synthesis of proteasome subunit genes in response to proteasome inhibition, promotes the recovery of proteasome activity, thus mitigating proteotoxic stress and enhancing cellular survival. However, whether or not the Nrf1 pathway is active in AD neurons experiencing proteotoxic stress is currently unclear. Using cell line-based models of AD, here we propose to interrogate the functional status of the Nrf1 pathway. Also, using a loss-of-function genetic screen, we propose to uncover kinase(s) that could act as negative regulator(s) of the Nrf1 pathway. If successful, our studies could help elucidate the role of the Nrf1 pathway in AD-afflicted neuronal cells and set the stage for future studies aimed at developing novel therapeutics to boost neuronal protein degradation pathways to enable tau clearance and thereby mitigate proteotoxic stress.