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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 neurodegenerativeproteinopathy characterized by progressive motor neuronal loss, misfolding, aggregation and deposition of TDP-43 protein in the central nervous system (CNS), and the development of chronic neuroinflammation. Currently, it is thought that these proteins in their pathological forms could cause microglia-mediated neuroinflammation. However, the underlying mechanisms remain poorly understood and there is a clear need to identify novel therapeutic targets that may lead to the development of effective treatments. Recently, we identified the Ser/Thr kinase MOK as a key player in microglial cellular responses associated to TDP-43 pathological species, binding to cytoplasmic TDP-43 aggregates found to induce proinflammatory responses in microglial cells. The goal of this proposal is to study the role and molecular mechanisms of MOK in neuroinflammation in the context of ALS.

Results: Throughout this project we have investigated the signaling pathways in the TDP^-43 aggregates-induced microglial responses and in a wider inflammation context, in which MOK may be involved, by means of high-throughput RNA sequencing (RNA-Seq) and interactomics studies. In addition, we have analyzed the protein expression levels and phosphorylation state of MOK in spinal cord tissue slides from TDP-43 transgenic mice and from ALS patients by immmunohistochemistry (IHC) and in isolated spinal microglial cells from SOD1 pre-clinical model mice, observing significant differences compared to healthy controls. Moreover, we have identified by coimmunoprecipitation, Western blot and immunofluorescence (IF) a number of MOKregulated proteins, potential therapeutic targets for dysregulated neuroinflammation and ALS. Finally, the generation and use of MOK-knockout (KO) microglial cells and, soon, of MOK-KO mice, have enabled us to explore a role for MOK in global transcriptional regulation in inflammatory responses of glial cells.

 

Scientific Production
 
Magazine Articles 5
Communications at national conferences 1
Communications at international conferences 4

 

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