ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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67 citing papers in PubMed, 112 citations in OpenAlex.
- Downregulation of dual-specificity phosphatase 1 (DUSP1) in post-mortem brain white matter in progressive multiple sclerosis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026Article
- Survival motor neuron protein-independent amelioration of spinal muscular atrophy by pharmacological inhibition of c-Jun-NHBrain communications · 2026Article
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- KChIP3 fosters neuroinflammation and synaptic dysfunction in the 5XFAD mouse model of Alzheimer's disease.Journal of neuroinflammation · 2025Article
- Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.Signal transduction and targeted therapy · 2025Review
- Down-regulation of microRNA-382-5p reduces neuropathic pain by targeting regulation of dual specificity phosphatase-1.The Korean journal of pain · 2024Article
- Toxic effects of mutant huntingtin in axons are mediated by its proline-rich domain.Brain : a journal of neurology · 2024Article
- DUSP1/MKP-1 represents another piece in the P2X7R intracellular signaling puzzle in cerebellar cells: our last journey with Mª Teresa along the purinergic pathways of Eden.Purinergic signalling · 2024Article
- Regulatory mechanism of circular RNAs in neurodegenerative diseases.CNS neuroscience & therapeutics · 2024Review
- Role of N-formyl peptide receptor 2 in germinal matrix hemorrhage: an intrinsic review of a hematoma resolving pathway.Neural regeneration research · 2024Review
- Transcriptome analysis of the cerebral cortex of acrylamide-exposed wild-type and IL-1β-knockout mice.Archives of toxicology · 2024Article
- mPFC DUSP1 mediates adolescent cocaine exposure-induced higher sensitivity to drug in adulthood.EMBO reports · 2023Article
- P38 MAPK Signaling in the Retina: Effects of Aging and Age-Related Macular Degeneration.International journal of molecular sciences · 2023Article
- Blood transcriptomic signatures associated with molecular changes in the brain and clinical outcomes in Parkinson's disease.Nature communications · 2023Article
- A Comprehensive Bioinformatics Approach to Identify Molecular Signatures and Key Pathways for the Huntington Disease.Bioinformatics and biology insights · 2023Article
- Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington's Disease.International journal of molecular sciences · 2022Article
- Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer's disease.Neuron · 2022Article
- Degalactosylated Whey Protein Suppresses Inflammatory Responses Induced by Lipopolysaccharide in Mice.Frontiers in nutrition · 2022Article
- The MAP Kinase Phosphatase MKP-1 Modulates Neurogenesis via Effects on BNIP3 and Autophagy.Biomolecules · 2021Article
- circRNA Regulates Dopaminergic Synapse, MAPK, and Long-term Depression Pathways in Huntington Disease.Molecular neurobiology · 2021Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
Abstract
We previously demonstrated that sodium butyrate is neuroprotective in Huntington's disease (HD) mice and that this therapeutic effect is associated with increased expression of mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1/DUSP1). Here we show that enhancing MKP-1 expression is sufficient to achieve neuroprotection in lentiviral models of HD. Wild-type MKP-1 overexpression inhibited apoptosis in primary striatal neurons exposed to an N-terminal fragment of polyglutamine-expanded huntingtin (Htt171-82Q), blocking caspase-3 activation and significantly reducing neuronal cell death. This neuroprotective effect of MKP-1 was demonstrated to be dependent on its enzymatic activity, being ablated by mutation of its phosphatase domain and being attributed to inhibition of specific MAP kinases (MAPKs). Overexpression of MKP-1 prevented the polyglutamine-expanded huntingtin-induced activation of c-Jun N-terminal kinases (JNKs) and p38 MAPKs, whereas extracellular signal-regulated kinase (ERK) 1/2 activation was not altered by either polyglutamine-expanded Htt or MKP-1. Moreover, mutants of MKP-1 that selectively prevented p38 or JNK binding confirmed the important dual contributions of p38 and JNK regulation to MKP-1-mediated neuroprotection. These results demonstrate additive effects of p38 and JNK MAPK inhibition by MKP-1 without consequence to ERK activation in this striatal neuron-based paradigm. MKP-1 also provided neuroprotection in vivo in a lentiviral model of HD neuropathology in rat striatum. Together, these data extend previous evidence that JNK- and p38-mediated pathways contribute to HD pathogenesis and, importantly, show that therapies simultaneously inhibiting both JNK and p38 signaling pathways may lead to improved neuroprotective outcomes.
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