{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T18:51:19Z","timestamp":1789411879555,"version":"build-2803163510"},"reference-count":47,"publisher":"Society for Neuroscience","issue":"22","license":[{"start":{"date-parts":[[2012,11,30]],"date-time":"2012-11-30T00:00:00Z","timestamp":1354233600000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2012,5,30]]},"abstract":"<jats:p>Huntington's disease (HD) is caused by a mutation in the huntingtin (<jats:italic>htt<\/jats:italic>) gene encoding an expansion of glutamine repeats at the N terminus of the Htt protein. Proteolysis of Htt has been identified as a critical pathological event in HD models. In particular, it has been postulated that proteolysis of Htt at the putative caspase-6 cleavage site (at amino acid Asp-586) plays a critical role in disease progression and pathogenesis. However, whether caspase-6 is indeed the essential enzyme that cleaves Htt at this site<jats:italic>in vivo<\/jats:italic>has not been determined. To evaluate, we crossed the BACHD mouse model with a caspase-6 knock-out mouse (<jats:italic>Casp6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>). Western blot and immunocytochemistry confirmed the lack of caspase-6 protein in<jats:italic>Casp6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice, regardless of HD genotype. We predicted the<jats:italic>Casp6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mouse would have reduced levels of caspase-6 Htt fragments and increased levels of full-length Htt protein. In contrast, we found a significant reduction of full-length mutant Htt (mHtt) and fragments in the striatum of BACHD<jats:italic>Casp6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice. Importantly, we detected the presence of Htt fragments consistent with cleavage at amino acid Asp-586 of Htt in the BACHD<jats:italic>Casp6<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mouse, indicating that caspase-6 activity cannot fully account for the generation of the Htt 586 fragment<jats:italic>in vivo<\/jats:italic>. Our data are not consistent with the hypothesis that caspase-6 activity is critical in generating a potentially toxic 586 aa Htt fragment<jats:italic>in vivo<\/jats:italic>. However, our studies do suggest a role for caspase-6 activity in clearance pathways for mHtt protein.<\/jats:p>","DOI":"10.1523\/jneurosci.6379-11.2012","type":"journal-article","created":{"date-parts":[[2012,5,30]],"date-time":"2012-05-30T18:59:42Z","timestamp":1338404382000},"page":"7454-7465","source":"Crossref","is-referenced-by-count":42,"title":["Caspase-6 Activity in a BACHD Mouse Modulates Steady-State Levels of Mutant Huntingtin Protein But Is Not Necessary for Production of a 586 Amino Acid Proteolytic Fragment"],"prefix":"10.1523","volume":"32","author":[{"given":"Juliette","family":"Gafni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodora","family":"Papanikolaou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"DeGiacomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Holcomb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Menalled","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Kudwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Fitzpatrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Ramboz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasi I.","family":"Tuunanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimmo K.","family":"Lehtim\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X. 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