Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease in which motor neurons degenerate and dye off. A typical pathological hallmark is the buildup of sustained neuroinflammation since early stages of disease and the presence of intracellular protein aggregates, mainly composed by TDP-43, which are thought to be able to trigger dysregulated inflammatory responses mediated by microglia. However, the molecular mechanisms, signaling pathways and upstream regulators of disease-associated microglial subpopulations (DAM, MgND) remain to be elucidated.

Recently, we have uncovered the signaling kinase MOK (MAPK/MAK/MRK overlapping kinase) as a key mediator of microglial inflammatory responses via de epigenetic reader Brd4, and have demonstrated that MOK is involved in ALS pathophysiology (Pérez-Cabello et al., PNAS 2023). Moreover, we have observed that prophylactic administration of a MOK inhibitor compound protects ALS modeling mice during the treatment (Pérez-Cabello et al., PNAS 2023). Based on these and other results, the main goals of this project are: i) to expand the knowledge on the mechanisms mediated by MOK in immune responses of microglia in the context of inflammation and ALS; ii) to evaluate the potential of MOK as a novel therapeutic target and biomarker in ALS.