P01 - Homeostasis

Neuronal proteostasis during neuroinflammation

Multiple sclerosis (MS) represents a prevalent inflammatory neurodegenerative disorder of the central nervous system (CNS) affecting millions worldwide. Despite advancements in immunomodulatory therapies, there remains an urgent need for neuroprotective interventions due to the persistent progression of neurodegeneration in MS. The exact mechanisms underlying inflammation-induced neurondegeneration remain elusive, warranting comprehensive investigation into understanding neuron-intrinsic responses to inflammatory challenges.

Here, we propose to elucidate the role of the ubiquitin-proteasome system (UPS) and its immunoproteasomal component in modulating neuronal viability during CNS inflammation. Through a combination of proteomic, transcriptomic, and ubiquitinomic profiling in mouse models of CNS inflammation, we aim to delineate the impact of UPS alterations on neuronal function. Furthermore, spatial deconstruction of proteasomal composition and activity within neurons will provide crucial insights into their role in mediating inflammatory stress responses. By targeting proteasomal components and downstream signaling pathways, we seek to identify key regulators of the neuronal stress network for future therapeutic interventions.

The anticipated outcomes of this project will not only enhance our understanding of UPS dynamics in inflamed neurons but also uncover novel targets for therapeutic intervention in MS and other diseases with inflammation-induced neurodegeneration. Additionally, this research will contribute to fundamental knowledge of neuronal proteasome metabolism, offering broader implications for understanding deregulated pathways in various neurodegenerative conditions.