{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:54:53Z","timestamp":1791658493140,"version":"4.3.4"},"reference-count":56,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"44","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:p>Recently, it has been shown that blocking the binding of valosin-containing protein (VCP) to mutant huntingtin (mtHtt) can prevent neuronal mitochondrial autophagy in Huntington\u2019s disease (HD) models. Herein, we describe the development and efficacy of a protein-like polymer (PLP) for inhibiting this interaction in cellular and in vivo models of HD. PLPs exhibit bioactivity in HD mouse striatal cells by successfully inhibiting mitochondrial destruction. PLP is notably resilient to in vitro enzyme, serum, and liver microsome stability assays, which render analogous control oligopeptides ineffective. PLP demonstrates a 2000-fold increase in circulation half-life compared to peptides, exhibiting an elimination half-life of 152 hours. In vivo efficacy studies in HD transgenic mice (R6\/2) confirm the superior bioactivity of PLP compared to free peptide through behavioral and neuropathological analyses. PLP functions by preventing pathologic VCP\/mtHtt binding in HD animal models; exhibits enhanced efficacy over the parent, free peptide; and implicates the PLP as a platform with potential for translational central nervous system therapeutics.<\/jats:p>","DOI":"10.1126\/sciadv.ado8307","type":"journal-article","created":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T13:59:14Z","timestamp":1730469554000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["Proteomimetic polymer blocks mitochondrial damage, rescues Huntington\u2019s neurons, and slows onset of neuropathology in vivo"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8305-9133","authenticated-orcid":true,"given":"Wonmin","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9668-7796","authenticated-orcid":true,"given":"Mara","family":"Fattah","sequence":"additional","affiliation":[{"name":"Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0494-4486","authenticated-orcid":true,"given":"Yutong","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0428-291X","authenticated-orcid":true,"given":"Matthew P.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3996-3352","authenticated-orcid":true,"given":"Kendal P.","family":"Carrow","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA."},{"name":"Medical Scientist Training Program, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4047-7340","authenticated-orcid":true,"given":"Di","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0060-4683","authenticated-orcid":true,"given":"Zunren","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6637-1355","authenticated-orcid":true,"given":"Michael J.","family":"Avram","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8096-6291","authenticated-orcid":true,"given":"Keith","family":"Bailey","sequence":"additional","affiliation":[{"name":"Charles River Laboratories, Mattawan, MI 49071, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Or","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9578-3890","authenticated-orcid":true,"given":"Xin","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, OH 44106, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9945-5475","authenticated-orcid":true,"given":"Nathan C.","family":"Gianneschi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208, USA."},{"name":"Departments of Materials Science &amp; 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