Extracellular TDP‐43 aggregates target MAPK/MAK/MRK overlapping kinase (MOK) and trigger caspase‐3/IL‐18 signaling in microglia
Bibliographic record
Abstract
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‐1β, but also NLRP3dependent 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, 2797–2816 (2017). www.fasebj.org
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".