{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:42:51Z","timestamp":1791592971784,"version":"4.3.4"},"reference-count":32,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2025,6,22]],"date-time":"2025-06-22T00:00:00Z","timestamp":1750550400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Amyloid aggregation of \u03b1-Synuclein is a defining feature of several neurodegenerative disorders, including Parkinson's disease (PD), Lewy body dementia (LBD), and Alzheimer's disease (AD). While there have been many attempts to reduce the \u03b1-Synuclein burden of neuronal cells through direct targeting of the protein, the conformationally dynamic nature of \u03b1-Synuclein make it a particularly difficult target to drug. Given the correlation between \u03b1-Synuclein levels and both familial and environmentally induced synucleinopathies, targeting the \u03b1-Synuclein mRNA transcript offers an alternative therapeutic avenue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To develop and evaluate protein-based RNA-binding therapeutics (PROTEIMERs) that selectively bind the 5\u2032 untranslated region (UTR) of \u03b1-Synuclein mRNA and inhibit its translation to reduce \u03b1-Synuclein levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed high-throughput phage display to identify novel RNA-binding PROTEIMER candidates targeting the 5\u2032UTR of \u03b1-Synuclein mRNA. Binding affinities were assessed via surface plasmon resonance (SPR). Computational structural predictions were used to evaluate PROTEIMER-RNA interactions relative to known regulatory proteins IRP1 and IRP2. RNase domains were fused to the lead PROTEIMERs, and their RNA degradation activity was tested in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Three PROTEIMERs were identified that bind the \u03b1-Synuclein 5\u2032UTR with high affinity. Structural predictions supported specific interactions with the structured RNA region. RNase-fused PROTEIMERs demonstrated targeted RNA degradation and induced decay of \u03b1-Synuclein mRNA in vitro, indicating translational suppression capability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings demonstrate the feasibility of using engineered protein therapeutics to target \u03b1-Synuclein mRNA via the 5\u2032UTR. These PROTEIMERs represent a promising new strategy for reducing \u03b1-Synuclein levels and mitigating neurodegenerative progression in LBD, PD, and AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251351305","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:23:17Z","timestamp":1750638197000},"page":"1187-1197","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting \u03b1-synuclein translation: Novel PROTEIMERs as 5\u2019-UTR directed inhibitors"],"prefix":"10.1177","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1694-1652","authenticated-orcid":false,"given":"Logan S","family":"Richards","sequence":"first","affiliation":[{"name":"CrossLife Technologies Inc., Carlsbad, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Kim","sequence":"additional","affiliation":[{"name":"CrossLife Technologies Inc., Carlsbad, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5289-5703","authenticated-orcid":false,"given":"Hannah K","family":"Cho","sequence":"additional","affiliation":[{"name":"CrossLife Technologies Inc., Carlsbad, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0721-0575","authenticated-orcid":false,"given":"Catherine M","family":"Cahill","sequence":"additional","affiliation":[{"name":"Neurochemistry Laboratory, Massachusetts General Hospital (East), and Harvard Medical School, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1262-8578","authenticated-orcid":false,"given":"Jack T","family":"Rogers","sequence":"additional","affiliation":[{"name":"Neurochemistry Laboratory, Massachusetts General Hospital (East), and Harvard Medical School, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1654-0098","authenticated-orcid":false,"given":"HyunDae D","family":"Cho","sequence":"additional","affiliation":[{"name":"CrossLife Technologies Inc., Carlsbad, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,6,22]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0123444"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121898"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906277106"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.14802\/jmd.11001"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2306682120"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2024.134417"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-010-0513-5"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1905057117"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST0361282"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.160022"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/WNR.0b013e328354a1f0"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4001937"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjz091"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.93"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2154"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.4c00472"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.211439598"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_3_3_20_2","unstructured":"Schr\u00f6dinger L DeLano W. 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