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Experimental evidence suggests that GABAergic medium-sized spiny neurons (MSNs) in the striatum are particularly vulnerable to glutamate-induced toxicity (excitotoxicity) and its analogues. However, the molecular mechanisms underlying MSN-specific death in HD remain poorly understood. The serine\/threonine protein kinase D1 (PKD1) confers neuroprotection in various neuropathological conditions, including ischemic stroke. While excitotoxicity inactivates PKD1 in cortical glutamatergic neurons without altering its levels, active PKD1 potentiates the survival of excitatory neurons in highly excitotoxic environments. Here, we investigated whether PKD1 activity dysregulation contributes to MSN death in HD and its association with neurodegeneration. We found an unexpected reduction in PKD1 protein levels in striatal neurons from HD patients. Similarly, the R6\/1 mouse model of HD exhibited progressive PKD1 protein loss, commencing at early disease stages, accompanied by decreased <jats:italic>Prkd1<\/jats:italic> transcript levels. PKD1 downregulation also occurred in the cerebral cortex of R6\/1 mice, but only at late stages. Functionally, pharmacological PKD inhibition in primary striatal neurons exacerbated excitotoxic damage and apoptosis induced by glutamate N-methyl D-aspartate (NMDA) receptors, whereas expression of constitutively active PKD1 (PKD1-Ca) conferred neuroprotection. Furthermore, PKD1-Ca protected against polyQ-induced apoptosis in a cellular model of HD. In a translational approach, intrastriatal lentiviral delivery of PKD1-Ca in symptomatic R6\/1 mice prevented the loss of DARPP-32, a molecular marker of MSNs. Collectively, our findings strongly suggest that PKD1 loss-of-function contributes to HD pathogenesis and the selective vulnerability of MSNs. These findings position PKD1 as a promising therapeutic target for mitigating MSN death in HD.<\/jats:p>","DOI":"10.1038\/s41419-025-07688-9","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T06:01:33Z","timestamp":1748930493000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Down-regulation of neuroprotective protein kinase D in Huntington\u00b4s disease"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9810-2165","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Sebasti\u00e1n-Serrano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0639-4592","authenticated-orcid":false,"given":"Ana","family":"Sim\u00f3n-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2725-6228","authenticated-orcid":false,"given":"Mar\u00eda","family":"Santos-Galindo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1563-3316","authenticated-orcid":false,"given":"Marina Prudencio","family":"S\u00e1nchez-Carralero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7946-9861","authenticated-orcid":false,"given":"Alberto","family":"H.-Alc\u00e1ntara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5831-9132","authenticated-orcid":false,"given":"Cristina","family":"Clemente","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5009-344X","authenticated-orcid":false,"given":"Julia","family":"Pose-Utrilla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1410-8621","authenticated-orcid":false,"given":"Miguel R.","family":"Campanero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0934-9711","authenticated-orcid":false,"given":"Eva","family":"Porlan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1597-3916","authenticated-orcid":false,"given":"Jos\u00e9 J.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4326-9005","authenticated-orcid":false,"given":"Teresa","family":"Iglesias","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"7688_CR1","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1056\/NEJM198611133152006","volume":"315","author":"JB Martin","year":"1986","unstructured":"Martin JB, Gusella JF. 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