MAP Kinase Phosphatase 1 (MKP-1/DUSP1) Is Neuroprotective in Huntington's Disease via Additive Effects of JNK and p38 Inhibition

• DOI: 10.1523/jneurosci.4965-11.2013
• Publication Date: 2013-02-07T12:37:47Z
• Authors: David M. Taylor; Roger Moser; Etienne Régulier; Lionel Breuillaud; Meredith Dixon; Ayshe Ana Beesen; Linda Elliston; Mariana de Fatima...; Jinho Kim; Lesley Jones; Darlene R. Goldstein; Robert J. Ferrante; Ruth Luthi-Carter
• Keywords: 0301 basic medicine; 0303 health sciences; MAP Kinase Kinase 4; Dual Specificity Phosphatase 1; p38 Mitogen-Activated Protein Kinases; Rats; Mice; 03 medical and health sciences; Huntington Disease; Neuroprotective Agents; Animals; Female; Rats, Wistar; Cells, Cultured

We previously demonstrated that sodium butyrate is neuroprotective in Huntington's disease (HD) mice and this therapeutic effect associated with increased expression of mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1/DUSP1). Here we show enhancing MKP-1 sufficient to achieve neuroprotection lentiviral models HD. Wild-type overexpression inhibited apoptosis primary striatal neurons exposed an N-terminal fragment polyglutamine-expanded huntingtin (Htt171–82Q), blocking caspase-3 activation significantly reducing neuronal cell death. This was be dependent on its enzymatic activity, being ablated by mutation domain attributed inhibition specific MAP kinases (MAPKs). Overexpression prevented the huntingtin-induced c-Jun (JNKs) p38 MAPKs, whereas extracellular signal-regulated kinase (ERK) 1/2 not altered either Htt or MKP-1. Moreover, mutants selectively JNK binding confirmed important dual contributions regulation MKP-1-mediated neuroprotection. These results demonstrate additive effects MAPK without consequence ERK neuron-based paradigm. also provided vivo a model HD neuropathology rat striatum. Together, these data extend previous evidence JNK- p38-mediated pathways contribute pathogenesis and, importantly, therapies simultaneously inhibiting both signaling may lead improved outcomes.