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While the C\u2010terminal 106\u2013126 peptide has been well studied for its role in prion replication and toxicity, the octapeptide repeat (OPR) sequence found within the N\u2010terminal domain has been relatively under explored. Recent findings that the OPR has both local and long\u2010range effects on prion protein folding and assembly, as well as its ability to bind and regulate transition metal homeostasis, highlights the important role this understudied region may have in prion pathologies. This review attempts to collate this knowledge to advance a deeper understanding on the varied physiologic and pathologic roles the prion OPR plays, and connect these findings to potential therapeutic modalities focused on OPR\u2010metal binding. Continued study of the OPR will not only elucidate a more complete mechanistic model of prion pathology, but may enhance knowledge on other neurodegenerative processes underlying Alzheimer's, Parkinson's, and Huntington's diseases.<\/jats:p>","DOI":"10.1002\/pep2.24303","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T09:22:59Z","timestamp":1675070579000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The manifold role of octapeptide repeats in prion protein assembly"],"prefix":"10.1002","volume":"115","author":[{"given":"Amy H.","family":"Guadagno","sequence":"first","affiliation":[{"name":"Nanomedicine, Intercollegiate Degree Program Pennsylvania State University  University Park Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5441-2164","authenticated-orcid":false,"given":"Scott H.","family":"Medina","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Pennsylvania State University  University Park Pennsylvania USA"},{"name":"Huck Institutes of the Life Sciences Pennsylvania State University  University Park Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,1,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/femspd\/ftv087"},{"issue":"1","key":"e_1_2_8_3_1","first-page":"1","volume":"50","author":"Liberski P. 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