title: MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition.
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.
authors: Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: David M
authors: DM
authors: Taylor
authors: Roger
authors: R
authors: Moser
authors: Etienne
authors: E
authors: Régulier
authors: Lionel
authors: L
authors: Breuillaud
authors: Meredith
authors: M
authors: Dixon
authors: Ayshe Ana
authors: AA
authors: Beesen
authors: Linda
authors: L
authors: Elliston
authors: Mariana de Fatima
authors: Mde F
authors: Silva Santos
authors: Jinho
authors: J
authors: Kim
authors: Lesley
authors: L
authors: Jones
authors: Darlene R
authors: DR
authors: Goldstein
authors: Robert J
authors: RJ
authors: Ferrante
authors: Ruth
authors: R
authors: Luthi-Carter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis*; D005260:Female; D006816:Huntington Disease / Q000201:enzymology* / Q000517:prevention & control*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse
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