Extracellular TDP‐43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase‐3/IL‐18 signaling in microglia

Abstract

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-1b, but also NLRP3-dependent and noncanonical IL-18 processing. Moreover, we report a link between TDP-43 and neuronal loss via the 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. FASEB J. 31, 2797FASEB J. 31, -2816FASEB J. 31, (2017

Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons

“…This represents the first in vivo demonstration of TDP-43 uptake by microglia as well as the prevention of TDP-43 spreading by normal microglia. Further study into the fate of TDP-43 and whether microglial function is altered following TDP-43 uptake in the zebrafish model may help expand upon the early evidence for microglial involvement in the progression of ALS/FTLD [8, 35, 46]. For example, phagocytosis of degradation-resistant TDP-43 aggregates [69] may disrupt the lysosomal pathway in microglia and, therefore, impair their ability for clearance of TDP-43.…”

Subarachnoid hemorrhage enhances the expression of TDP‑43 in the brain of experimental rats and human subjects

“…In addition, increased expression levels of TDP-43 in biological fluids, including CSF and plasma, have been detected in patients with amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration ( 20 ). Extracellular TDP-43 may be the result of cell death induced by TDP-43 inclusion bodies in the cytoplasm ( 21 ). In addition, TDP-43 can be released from cells by secretory vesicles, known as exosomes ( 22 , 23 ).…”

“…Inflammatory factors, including tumor necrosis factor-α and lipopolysaccharide, may promote the cytoplasmic accumulation of TDP-43 in neurons and glial cells, as suggested by the proteinopathy of TDP-43 in CNS-associated inflammatory diseases, including ALS ( 24 , 25 ). It has been reported that extracellular TDP-43 activates glial cells and induces the microglial caspase-3 and interleukin-18 signaling pathway, resulting in the formation of TDP-43 cytoplasmic inclusion bodies via reverse translocation of endogenous TDP-43 from the nucleus to the cytoplasm ( 21 ). Therefore, inflammation induced by SAH may account for the observed elevation in expression levels of TDP-43 within the CSF and brains of patients with SAH and experimental rats, respectively.…”

Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis

“…Among other immune‐related phenotypes, perturbed responses in MG were identified . Following earlier confirmation of TDP‐43 in the cerebrospinal fluid of patients with ALS , a recent study also demonstrated that extracellular TDP‐43 aggregates can trigger activation of the NF‐kB pathway in MG, invoking secretion of IL‐1b and IL‐18 . Interestingly, a MG‐specific inducible conditional TDP‐43 knockout mouse line resulted in significant synaptic loss, while enhancing amyloid clearance .…”