ArticleHuman molecular genetics2015
Opposing roles of p38 and JNK in a Drosophila model of TDP-43 proteinopathy reveal oxidative stress and innate immunity as pathogenic components of neurodegeneration.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
- Meta-analysis of Genetic Modifiers Reveals Candidate Dysregulated Pathways in Amyotrophic Lateral Sclerosis.Neuroscience · 2019Pooled it
- Loss of TDP-43 Drives Innate Immune Activation Through Relish inInternational journal of molecular sciences · 2026Article
- Toxic mechanisms of amyloid oligomers and therapeutic strategies.Protein science : a publication of the Protein Society · 2026Review
- Reduction of RAD23A extends lifespan and mitigates pathology in a mouse model of TDP-43 proteinopathy.Nature communications · 2026Article
- Excitotoxicity in amyotrophic lateral sclerosis: a key pathogenic mechanism.Brain communications · 2026Review
- Pyruvate kinase deficiency links metabolic perturbations to neurodegeneration and axonal protection.Molecular metabolism · 2025Article
- Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.Cell reports · 2025Article
- Drosophila glial system: an approach towards understanding molecular complexity of neurodegenerative diseases.Molecular biology reports · 2024Review
- Article
- TDP-43 pathology in Drosophila induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1.PLoS genetics · 2023Article
- Inhibition of the MEK/ERK pathway suppresses immune overactivation and mitigates TDP-43 toxicity in a Drosophila model of ALS.Immunity & ageing : I & A · 2023Article
- TDP-43 pathology inbioRxiv : the preprint server for biology · 2023Article
- Review
- Article
- Review
- Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Review
- Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis.Biomedicines · 2021Review
- TDP-43 and Inflammation: Implications for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.International journal of molecular sciences · 2021Review
- Insect Behavioral Change and the Potential Contributions of Neuroinflammation-A Call for Future Research.Genes · 2021Review
- Amyotrophic Lateral Sclerosis Genes inInternational journal of molecular sciences · 2021Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Pathological aggregation and mutation of the 43-kDa TAR DNA-binding protein (TDP-43) are strongly implicated in the pathogenesis amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 neurotoxicity has been extensively modeled in mice, zebrafish, Caenorhabditis elegans and Drosophila, where selective expression of TDP-43 in motoneurons led to paralysis and premature lethality. Through a genetic screen aimed to identify genetic modifiers of TDP-43, we found that the Drosophila dual leucine kinase Wallenda (Wnd) and its downstream kinases JNK and p38 influenced TDP-43 neurotoxicity. Reducing Wnd gene dosage or overexpressing its antagonist highwire partially rescued TDP-43-associated premature lethality. Downstream of Wnd, the JNK and p38 kinases played opposing roles in TDP-43-associated neurodegeneration. LOF alleles of the p38b gene as well as p38 inhibitors diminished TDP-43-associated premature lethality, whereas p38b GOF caused phenotypic worsening. In stark contrast, disruptive alleles of Basket (Bsk), the Drosophila homologue of JNK, exacerbated longevity shortening, whereas overexpression of Bsk extended lifespan. Among possible mechanisms, we found motoneuron-directed expression of TDP-43 elicited oxidative stress and innate immune gene activation that were exacerbated by p38 GOF and Bsk LOF, respectively. A key pathologic role for innate immunity in TDP-43-associated neurodegeneration was further supported by the finding that genetic suppression of the Toll/Dif and Imd/Relish inflammatory pathways dramatically extended lifespan of TDP-43 transgenic flies. We propose that oxidative stress and neuroinflammation are intrinsic components of TDP-43-associated neurodegeneration and that the balance between cytoprotective JNK and cytotoxic p38 signaling dictates phenotypic outcome to TDP-43 expression in Drosophila.
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