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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Authors | David M Taylor, Roger Moser, Etienne Régulier, Lionel Breuillaud, Meredith Dixon, Ayshe Ana Beesen, Linda Elliston, Mariana de Fatima Silva Santos, Jinho Kim, Lesley Jones, Darlene R Goldstein, Robert J Ferrante, Ruth Luthi-Carter |
Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience
(J Neurosci)
Vol. 33
Issue 6
Pg. 2313-25
(Feb 06 2013)
ISSN: 1529-2401 [Electronic] United States |
PMID | 23392662
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Neuroprotective Agents
- p38 Mitogen-Activated Protein Kinases
- MAP Kinase Kinase 4
- Dual Specificity Phosphatase 1
- Dusp1 protein, mouse
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Topics |
- Animals
- Cells, Cultured
- Dual Specificity Phosphatase 1
(biosynthesis)
- Female
- Huntington Disease
(enzymology, prevention & control)
- MAP Kinase Kinase 4
(antagonists & inhibitors, metabolism)
- Mice
- Neuroprotective Agents
(metabolism)
- Rats
- Rats, Wistar
- p38 Mitogen-Activated Protein Kinases
(antagonists & inhibitors, metabolism)
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