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), primary and KO-cell cultures, proteomics studies and protein-DNA interaction assays (ChIP-PCR). Our results demonstrate that MOK mediates the inflammatory and type-I IFN responses in microglia via mechanisms that involve the epigenetic reader Brd4 and modulate its function as a regulator of gene-expression. Moreover, our results indicate that MOK is altered in spinal cord cells in samples from both mouse models and ALS patients, pointing to a pathophysiological role of this signaling kinase in ALS disease.