Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia.
Dysregulated microglial responses are central in neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar disease (FTLD). Pathologic TDP-43, which is typically found in intracellular inclusions, is a misfolding protein with emerging roles in ALS and FTLD. Recently, TDP-43 species have been found in extracellular fluids of patients; however, the overall implications of TDP-43-mediated signaling linked to neuroinflammation are poorly understood. Our work-the first, to our knowledge, to focus on innate immunity responses to TDP-43 aggregates-shows that such species are internalized by microglia and cause abnormal mobilization of endogenous TDP-43. Exposure to TDP-43 aggregates elicited not only IL-1β, but also NLRP3-dependent and noncanonical IL-18 processing. Moreover, we report a link between TDP-43 and neuronal lossviathe apoptosis-independent emerging roles of caspase-3 in neurotoxic inflammation. Our results further support the view of noncell autonomous neurodegenerative mechanisms in ALS. Remarkably, we demonstrate that TDP-43 aggregates bind to and colocalize with MAPK/MAK/MRK overlapping kinase (MOK) and show that its phosphorylation status is disrupted. Finally, we show that this TDP-43-caused activation state can be altered by exogenous Hsp27 and Hsp70 chaperones. Our study provides new insight into the immune phenotype, mechanisms, and signaling pathways that operate in microglial neurotoxic activation in ALS.-Leal-Lasarte, M. M., Franco, J. M., Labrador-Garrido, A., Pozo, D., Roodveldt, C. Extracellular TDP-43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase-3/IL-18 signaling in microglia.
Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Seville-Spanish Research Council (CSIC)-University Paplo de Olavide, Seville, Spain; Seville, Spain.
María M
MM
Leal-Lasarte
Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Seville-Spanish Research Council (CSIC)-University Paplo de Olavide, Seville, Spain; Seville, Spain.|Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Seville, Spain.
Jaime M
JM
Franco
Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Seville-Spanish Research Council (CSIC)-University Paplo de Olavide, Seville, Spain; Seville, Spain.|Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Seville, Spain.
Adahir
A
Labrador-Garrido
Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Seville-Spanish Research Council (CSIC)-University Paplo de Olavide, Seville, Spain; Seville, Spain.|Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Seville, Spain.
David
D
Pozo
Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Seville-Spanish Research Council (CSIC)-University Paplo de Olavide, Seville, Spain; Seville, Spain; cintia.roodveldt@cabimer.es.
Cintia
C
Roodveldt
D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D053148:Caspase 3; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D020928:Mitogen-Activated Protein Kinases; C578077:Tardbp protein, mouse; C498977:Mok protein, mouse
amyotrophic lateral sclerosis; heat-shock protein; innate immunity; neurodegeneration; neuroinflammation