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Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain\u2010overactivation, among others. Kinase D\u2010interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat\u2010rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy\u2010terminal length and critical protein\u2010protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220\u2010C32) and the recently identified exon 33 (Kidins220\u2010C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220\u2010C33 as a form detrimental for neurons. However, the functional role of Kidins220\u2010C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220\u2010C33, in the striatum of HD patients, as well as in the R6\/1 HD mouse model starting at early symptomatic stages. These changes are C33\u2010specific as Kidins220\u2010C32 variant remains unchanged. We also find the early decrease in Kidins220\u2010C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using <jats:italic>ex vivo<\/jats:italic> assays and primary neurons, we demonstrate that Kidins220\u2010C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain\u2010mediated Kidins220\u2010C33 proteolysis modulates onset and\/or progression of HD.<\/jats:p>","DOI":"10.1111\/bpa.12761","type":"journal-article","created":{"date-parts":[[2019,7,2]],"date-time":"2019-07-02T09:50:54Z","timestamp":1562061054000},"page":"120-136","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Differential regulation of Kidins220 isoforms in Huntington's disease"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9810-2165","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Sebasti\u00e1n\u2010Serrano","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d, Consejo Superior de Investigaciones Cient\u00edficas\u2010Universidad Aut\u00f3noma de Madrid (CSIC\u2010UAM) Madrid Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red 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