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Functional characterization and mechanisms of the signalling kinase MOK in neuroinfiammation associated to Amyotrophic Lateral Sclerosis (ALS)

19th national competition for scientific and technical research

Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS): Molecular Etiology and Novel Treatments

Senior Researcher : Cintia Roodveldt

Research Centre or Institution : Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER)

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative proteinopathy characterized by misfolding, aggregation and deposition ofTDP-43 protein in CNS cells, as found in virtually all ALS patients and recently in the SODI G93. A mouse model, and is accompanied by the development of chronic neuroinflammation and motor neuron loss. Currently, it is thought that these proteins, in their pathologic form, may cause sustained microglial-mediated neuroinflammation within the CNS. However, the underlying pathogenic mechanisms are still not completely understood while there is a clear need for new therapeutic targets that could potentially lead to effective treatments. We have recently identified MAPKIMAKIMRK overlapping kinase (MOK), a Ser/Thr protein kinase, as a main player in microglial inflammatory response linked to pathological TDP-43 species. In particular, we found that MOK, a virtually uncharacterized signalling kinase, binds to TDP-43 aggregates within microglial cells, altering MOK's activity and affecting microglial proinflammatory responses, therefore pointing to a key role of MOK in neuroinflammation. The goal ofthis proposal is to study the role and molecular mechanism ofMOK in neuroinflammation by molecular characterization ofMOK signalling pathways in CNS cells, and immune profiling and transcriptomics analysis of microglia.

To this porpuse, we will use ALS cellular models, as well as samples from ALS patients and SODIG9 JA mice. Finally, we planto test the possible protective effect oftargeting MOK with a specific MOK inhibitor and through genetic ablation approaches, by assessing neuroinflammation, motor neurodegeneration, and disease course in a well-established ALS pre-clinical model.

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