MAP Kinase Phosphatase 1 (MKP-1/DUSP1) Is Neuroprotective in Huntington's Disease via Additive Effects of JNK and p38 Inhibition
| Autor: | Linda Anne Elliston, Roger Moser, Darlene R. Goldstein, Ruth Luthi-Carter, Ayshe Ana Beesen, Lionel Breuillaud, Mariana de Fatima Silva Santos, Lesley Jones, Etienne Régulier, Jinho Kim, David Taylor, Meredith Dixon, Robert J. Ferrante |
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| Rok vydání: | 2013 |
| Předmět: |
MAPK/ERK pathway
Huntingtin MAP Kinase Kinase 4 p38 mitogen-activated protein kinases Biology Neuroprotection p38 Mitogen-Activated Protein Kinases Article 03 medical and health sciences Mice 0302 clinical medicine Animals Rats Wistar Protein kinase A Cells Cultured 030304 developmental biology 0303 health sciences MAP kinase kinase kinase Kinase General Neuroscience Dual Specificity Phosphatase 1 Cell biology Rats Huntington Disease Neuroprotective Agents MAP kinase phosphatase Female 030217 neurology & neurosurgery |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience |
| DOI: | 10.1523/JNEUROSCI.4965-11.2013 |
| Popis: | 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 neuroprotectionin vivoin 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. |
| Databáze: | OpenAIRE |
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