{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:40:07Z","timestamp":1785400807884,"version":"3.56.0"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"29","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM147498"],"award-info":[{"award-number":["R35GM147498"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013301","name":"Parkinson\u2019s Foundation","doi-asserted-by":"publisher","award":["PF-IMP-1045798"],"award-info":[{"award-number":["PF-IMP-1045798"]}],"id":[{"id":"10.13039\/100013301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013301","name":"Parkinson\u2019s Foundation","doi-asserted-by":"publisher","award":["PF-JFA-1933"],"award-info":[{"award-number":["PF-JFA-1933"]}],"id":[{"id":"10.13039\/100013301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012443","name":"Maryland Stem Cell Research Fund","doi-asserted-by":"publisher","award":["2019-MSCRFD-4292"],"award-info":[{"award-number":["2019-MSCRFD-4292"]}],"id":[{"id":"10.13039\/100012443","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012443","name":"Maryland Stem Cell Research Fund","doi-asserted-by":"publisher","award":["2024-MSCRFD-6394"],"award-info":[{"award-number":["2024-MSCRFD-6394"]}],"id":[{"id":"10.13039\/100012443","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,21]]},"abstract":"<jats:p>\n                    \u03b1-Synucleinopathies are devastating neurodegenerative diseases characterized by pathological accumulation of a neuronal protein, \u03b1-synuclein (\u03b1Syn). Lowering soluble \u03b1Syn levels is a promising therapeutic strategy to limit aggregation and neurotoxicity, but directly targeting this protein is hindered by its intrinsically disordered structure and other factors, such as its conformational heterogeneity and intracellular drug delivery barriers. Consequently, increasing attention has been directed toward targeting the\n                    <jats:italic toggle=\"yes\">SNCA<\/jats:italic>\n                    transcript, which encodes \u03b1Syn. Here, we developed phosphorodiamidate morpholino oligonucleotide (PMO)-based RNA-degrading chimeras (RDCs) that selectively bind the 5\u2032 untranslated region of\n                    <jats:italic toggle=\"yes\">SNCA<\/jats:italic>\n                    messenger RNA (mRNA) and recruit RNase L for targeted RNA degradation. Through the systematic evaluation of nine RDCs, we identified and optimized 4-D1, which effectively reduced\n                    <jats:italic toggle=\"yes\">SNCA<\/jats:italic>\n                    mRNA and \u03b1Syn protein expression in HEK293T cells in an RNase L-dependent manner. 4-D1 lowered\n                    <jats:italic toggle=\"yes\">SNCA<\/jats:italic>\n                    transcript and \u03b1Syn protein levels in both primary cortical neurons from humanized\n                    <jats:italic toggle=\"yes\">SNCA<\/jats:italic>\n                    mice and in human induced pluripotent stem cell\u2013derived cortical neurons. This reduction prevented prion-like seeding induced by patient-derived \u03b1Syn fibrils and protected neurons from fibril-induced cytotoxicity. Finally, in vivo studies confirmed the efficacy of 4-D1 in reducing \u03b1Syn mRNA expression in humanized\n                    <jats:italic toggle=\"yes\">SNCA<\/jats:italic>\n                    mice. These findings indicate that PMO-based RDCs may represent a promising therapeutic modality for \u03b1-synucleinopathies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2526461123","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T16:17:56Z","timestamp":1784045876000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Targeted \u03b1-synuclein mRNA degradation by PMO-based RNA-degrading chimeras"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3410-8509","authenticated-orcid":false,"given":"Ning","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine","place":["Baltimore"]},{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Section of Genetic Medicine, Department of Medicine, Biological Sciences Division, University of Chicago","place":["Chicago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalakha","family":"Hegde","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Neurology, Johns Hopkins University School of Medicine","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Tang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Neurology, Johns Hopkins University School of Medicine","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiqing","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine","place":["Baltimore"]},{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Section of Genetic Medicine, Department of Medicine, Biological Sciences Division, University of Chicago","place":["Chicago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Feng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of 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Snyder Department of Neuroscience, Johns Hopkins University School of Medicine","place":["Baltimore"]},{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine","place":["Baltimore"]},{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for NanoBioTechnology, Johns Hopkins University","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6427-7485","authenticated-orcid":false,"given":"Alexander","family":"Pantelyat","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Section of Genetic Medicine, Department of Medicine, Biological Sciences Division, University of Chicago","place":["Chicago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana S.","family":"Rosenthal","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Section of Genetic Medicine, Department of Medicine, Biological Sciences Division, University of Chicago","place":["Chicago"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyao","family":"Ying","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Section of Genetic Medicine, Department of Medicine, Biological Sciences Division, University of Chicago","place":["Chicago"]},{"id":[{"id":"https:\/\/ror.org\/05q6tgt32","id-type":"ROR","asserted-by":"publisher"}],"name":"Hugo W. 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