{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T01:50:34Z","timestamp":1791078634795,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,4,2]],"date-time":"2014-04-02T00:00:00Z","timestamp":1396396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["MOP-12699"],"award-info":[{"award-number":["MOP-12699"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"CIHR-Huntington Society of Canada"},{"name":"Cure Huntington Disease Initiative"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["MH091037"],"award-info":[{"award-number":["MH091037"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["MH52711"],"award-info":[{"award-number":["MH52711"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Striatal neurodegeneration and synaptic dysfunction in Huntington's disease are mediated by the mutant huntingtin (mHtt) protein. MHtt disrupts calcium homeostasis and facilitates excitotoxicity, in part by altering NMDA receptor (NMDAR) trafficking and function. Pre\u2010symptomatic (excitotoxin\u2010sensitive) transgenic mice expressing full\u2010length human mHtt with 128 polyglutamine repeats (YAC128 Huntington's disease mice) show increased calpain activity and extrasynaptic NMDAR (Ex\u2010NMDAR) localization and signaling. Furthermore, Ex\u2010NMDAR stimulation facilitates excitotoxicity in wild\u2010type cortical neurons via calpain\u2010mediated cleavage of STriatal\u2010Enriched protein tyrosine Phosphatase 61 (STEP61). The cleavage product, STEP33, cannot dephosphorylate p38 mitogen\u2010activated protein kinase (MAPK), thereby augmenting apoptotic signaling. Here, we show elevated extrasynaptic calpain\u2010mediated cleavage of STEP61 and p38 phosphorylation, as well as STEP61 inactivation and reduced extracellular signal\u2010regulated protein kinase 1\/2 phosphorylation (ERK1\/2) in the striatum of 6\u2010week\u2010old, excitotoxin\u2010sensitive YAC128 mice. Calpain inhibition reduced basal and NMDA\u2010induced STEP61 cleavage. However, basal p38 phosphorylation was normalized by a peptide disrupting NMDAR\u2010post\u2010synaptic density protein\u201095 (PSD\u201095) binding but not by calpain inhibition. In 1\u2010year\u2010old excitotoxin\u2010resistant YAC128 mice, STEP33 levels were not elevated, but STEP61 inactivation and p38 and ERK 1\/2 phosphorylation levels were increased. These results show that in YAC128 striatal tissue, enhanced NMDAR\u2013PSD\u201095 interactions contributes to elevated p38 signaling in early, excitotoxin\u2010sensitive stages, and suggest that STEP61 inactivation enhances MAPK signaling at late, excitotoxin\u2010resistant stages.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12700-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>The YAC128 Huntington's disease mouse model shows early, enhanced susceptibility to NMDA receptor\u2010mediated striatal apoptosis, progressing to late\u2010stage excitotoxicity resistance. This study shows that elevated NMDA receptor\u2013PSD\u201095 interactions as well as decreased extrasynaptic STriatal\u2010Enriched protein tyrosine Phosphatase 61 (STEP61) activation may contribute to early enhanced apoptotic signaling. In late\u2010stage YAC128 mice, reduced STEP61 levels and activity correlate with elevated MAPK signaling, consistent with excitotoxicity resistance. Solid and dotted arrows indicate conclusions drawn from the current study and other literature, respectively.<\/jats:p>","DOI":"10.1111\/jnc.12700","type":"journal-article","created":{"date-parts":[[2014,3,3]],"date-time":"2014-03-03T11:46:20Z","timestamp":1393847180000},"page":"145-159","source":"Crossref","is-referenced-by-count":32,"title":["Alterations in STriatal\u2010Enriched protein tyrosine Phosphatase expression, activation, and downstream signaling in early and late stages of the <scp>YAC<\/scp>128 Huntington's disease mouse model"],"prefix":"10.1111","volume":"130","author":[{"given":"Clare M.","family":"Gladding","sequence":"first","affiliation":[{"name":"Department of Psychiatry Division of Neuroscience Brain Research Centre University of British Columbia Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Division of Neuroscience Brain Research Centre University of British Columbia Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily Y. 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