{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:08:48Z","timestamp":1791198528253,"version":"4.1.0"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"42","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,10,16]]},"abstract":"<jats:p>\n                    Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine expansion within huntingtin protein. The exact pathological mechanisms determining disease onset and progression remain unclear. However, aggregates of insoluble mutant huntingtin (mhtt), a hallmark of HD, are readily detected within neurons in HD brain. Although aggregated polyglutamines may not be inherently toxic, they constitute a biomarker for mutant huntingtin useful for developing therapeutics. We previously reported that the small molecule, C2-8, inhibits polyglutamine aggregation in cell culture and brain slices and rescues degeneration of photoreceptors in a\n                    <jats:italic>Drosophila<\/jats:italic>\n                    model of HD. In this study, we assessed the therapeutic potential of C2-8 in the R6\/2 mouse model of HD, which has been used to provide proof-of-concept data in considering whether to advance therapies to human HD. We show that, at nontoxic doses, C2-8 penetrates the blood\u2013brain barrier and is present in brain at a high concentration. C2-8-treated mice showed improved motor performance and reduced neuronal atrophy and had smaller huntingtin aggregates. There have been no prior drug-like, non-toxic, brain-penetrable aggregation inhibitors to arise from cell-based high-throughput screens for reducing huntingtin aggregation that is efficacious in preclinical\n                    <jats:italic>in vivo<\/jats:italic>\n                    models. C2-8 provides an essential tool to help elucidate mechanisms of neurodegeneration in HD and a therapeutic lead for further optimization and development.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0707842104","type":"journal-article","created":{"date-parts":[[2007,10,9]],"date-time":"2007-10-09T20:53:57Z","timestamp":1191963237000},"page":"16685-16689","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":96,"title":["A small-molecule therapeutic lead for Huntington's disease: Preclinical pharmacology and efficacy of C2-8 in the R6\/2 transgenic mouse"],"prefix":"10.1073","volume":"104","author":[{"given":"Vanita","family":"Chopra","sequence":"first","affiliation":[{"name":"*Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan H.","family":"Fox","sequence":"additional","affiliation":[{"name":"*Department 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