{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:19:22Z","timestamp":1791314362393,"version":"4.3.1"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"8","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,2,19]]},"abstract":"<jats:p>\n                    Aggregation of misfolded proteins is characteristic of a number of neurodegenerative diseases, including Huntington disease (HD). The CCT\/TRiC (chaperonin containing TCP-1\/TCP-1 ring) chaperonin complex can inhibit aggregation and cellular toxicity induced by expanded repeat Huntingtin (mHtt) fragments. The substrate-binding apical domain of CCT\/TRiC subunit CCT1, ApiCCT1, is sufficient to inhibit aggregation of expanded repeat mHtt fragments in vitro, providing therapeutic promise for HD. However, a key hurdle in considering ApiCCT1 as a potential treatment is in delivery. Because ApiCCT1 has a region of similarity to the HIV Tat protein cell-transduction domain, we tested whether recombinant ApiCCT1 (ApiCCT1\n                    <jats:sub>r<\/jats:sub>\n                    ) protein could enter cells following exogenous delivery and modulate an established panel of mHtt-mediated cell-based phenotypes. Cell fractionation studies demonstrate that exogenous ApiCCT1\n                    <jats:sub>r<\/jats:sub>\n                    can penetrate cell membranes and can localize to the nucleus, consistent with a strategy that can target both cytosolic and nuclear pathogenic events in HD. ApiCCT1\n                    <jats:sub>r<\/jats:sub>\n                    application does indeed modulate HD cellular phenotypes by decreasing formation of visible inclusions, fibrillar oligomers, and insoluble mHtt derived from expression of a truncated mHtt exon 1 fragment. ApiCCT1\n                    <jats:sub>r<\/jats:sub>\n                    also delays the onset of inclusion body formation as visualized via live imaging. ApiCCT1\n                    <jats:sub>r<\/jats:sub>\n                    reduces mHtt-mediated toxicity in immortalized striatal cells derived from full-length knock-in HD mice, suggesting that therapeutic benefit may extend beyond effects on aggregation. These studies provide the basis for a potentially robust and unique therapeutic strategy to target mHtt-mediated protein pathogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1222663110","type":"journal-article","created":{"date-parts":[[2013,1,30]],"date-time":"2013-01-30T23:58:57Z","timestamp":1359590337000},"page":"3077-3082","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":71,"title":["Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes"],"prefix":"10.1073","volume":"110","author":[{"given":"Emily M.","family":"Sontag","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry,"},{"name":"Department of Psychiatry and Human Behavior, and"},{"name":"Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz A.","family":"Joachimiak","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqun","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;"},{"name":"Department of Neurology, University of California Irvine School of Medicine, Irvine, CA 92697;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Housman","sequence":"additional","affiliation":[{"name":"Department of Biology,"},{"name":"Division of Health Sciences and Technology, and"},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142; 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