NEUROINFLAM-MS
Alzheimers (AD) and Parkinsons disease (PD) are prevalent neurodegenerative diseases, but their underlying mechanisms remain poorly understood. Emerging evidence suggests that neuroinflammation, characterized by the release of pro-inflammatory cytokines like IL-1, TNF-, and INF-, plays a pivotal role in these diseases, challenging the conventional focus on protein aggregates (A, Syn). In AD, it has been shown that elevated IL-1 levels induce the translocation of NEDD8 from the nucleus to the cytoplasm, where it co-localizes with the E3-ligase Parkin. Together with the kinase PINK1, Parkin is crucial for the removal of defective mitochondria, with loss-of-function mutations in these genes being the primary cause of early-onset PD. Intriguingly, phosphorylated NEDD8 can activate Parkin, implicating a more complex interconnection between neuroinflammation, NEDD8-and Parkin-regulated phosphorylation-dependent signaling in brain cells. Yet, a mechanistic understanding of cellular processes triggered by neuroinflammation remain elusive.This proposal aims to investigate spatiotemporal (phospho-)proteome changes in response to neuroinflammatory stress elicited by pro-inflammatory cytokines and Syn fibrils. To achieve this, I will combine spatial-proteomics using subcellular fractionation and hybrid-DIA in combination with the cutting-edge Orbitrap Astral mass spectrometer. Initial analyses of neuronal cell line models will be extended in a second step to hPSC derived neurons, astrocytes, microglia, and co-cultures thereof. This enhances the translational relevance by mimicking neuroinflammation in the complex tissue architecture of the brain. Finally, bioinformatically shortlisted neuroinflammation-regulated proteins and phospho-sites will be validated in cell-based models. With this project, I aspire to unravel the cellular mechanisms underlying neuroinflammation, potentially unlocking new avenues for therapeutic strategies against neurodegenerative diseases.
KOBENHAVNS UNIVERSITET (DK)