{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:45:31Z","timestamp":1792611931844,"version":"4.5.0"},"reference-count":56,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271563"],"award-info":[{"award-number":["82271563"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Parkinson's disease (PD) is characterized by the accumulation of Lewy bodies (LBs) in the brain, predominantly consisting of aggregated and phosphorylated \u03b1\u2010synuclein (\u03b1\u2010Syn). Consequently, strategies to suppress \u03b1\u2010Syn expression offer substantial therapeutic potential for PD. This study explores heteroduplex oligonucleotides (HDOs), an innovative gene\u2010silencing technology utilizing DNA\/RNA or DNA\/DNA hybrids. We designed two HDOs targeting \u03b1\u2010Syn: \u03b1\u2010Syn\u2010HDO\u20101 (DNA\/RNA) and \u03b1\u2010Syn\u2010HDO\u20102 (DNA\/DNA). Both demonstrated robust silencing of \u03b1\u2010Syn expression in mice. In AAV\u2010hSyn\u2010human SNCA\u2010treated mice, these \u03b1\u2010Syn\u2010HDOs exerted neuroprotective effects on dopaminergic neurons. Furthermore, they reduced aberrant \u03b1\u2010Syn accumulation in \u03b1\u2010Syn\u2010HEK293 cells and in mice treated with \u03b1\u2010Syn preformed fibrils (PFFs). The neuroprotective effects of \u03b1\u2010Syn\u2010HDOs were linked to activation of the brain\u2010derived neurotrophic factor (BDNF)\u2010tyrosine kinase B (TrkB) signaling pathway. Moreover, BDNF overexpression diminished abnormal \u03b1\u2010Syn aggregation in both PFFs\u2010treated \u03b1\u2010Syn\u2010HEK293 cells and PFFs\u2010treated mice. These results highlight the capacity of \u03b1\u2010Syn\u2010HDOs to protect dopaminergic neurons by enhancing BDNF\u2013TrkB signaling through the inhibition of abnormal elevated \u03b1\u2010Syn. Our findings position \u03b1\u2010Syn\u2010HDOs as promising therapeutic candidates for PD and suggest BDNF as a potential diagnostic biomarker or indicator of treatment efficacy.<\/jats:p>","DOI":"10.1111\/acel.70717","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:23:05Z","timestamp":1790162585000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of Abnormal Elevated \u03b1\u2010Synuclein Ameliorates Dopaminergic Neuron Degeneration in Parkinson's Disease Mouse Model"],"prefix":"10.1111","volume":"25","author":[{"given":"Xuenan","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Brain Science and Brain\u2010Inspired Research, Shandong Provincial Key Laboratory of Brain Science Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8877-4366","authenticated-orcid":false,"given":"Yiru","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine Jinan University  Guangzhou China"},{"name":"NHC Key Laboratory of Mental Health (Peking University), and National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth Hospital, Peking University Institute of Mental Health Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2440-1792","authenticated-orcid":false,"given":"Lujuan","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Brain Science and Brain\u2010Inspired Research, Shandong Provincial Key Laboratory of Brain Science Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Jinan China"},{"name":"Department of Physiology, School of Medicine Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xizhi","family":"Kang","sequence":"additional","affiliation":[{"name":"Institute of Brain Science and Brain\u2010Inspired Research, Shandong Provincial Key Laboratory of Brain Science Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Jinan China"},{"name":"Department of Neurosurgery Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6112-7385","authenticated-orcid":false,"given":"Xiwen","family":"Geng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1364-8730","authenticated-orcid":false,"given":"Fumika","family":"Sakaue","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Science Institute of Science Tokyo  Tokyo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Yokota","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Science Institute of Science Tokyo  Tokyo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3169-6314","authenticated-orcid":false,"given":"Liang\u2010wen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Brain Science and Brain\u2010Inspired Research, Shandong Provincial Key Laboratory of Brain Science Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Jinan China"},{"name":"Department of Neurosurgery Shandong Provincial Hospital Affiliated to Shandong First Medical University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yao","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6035-6867","authenticated-orcid":false,"given":"Ji\u2010chun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Brain Science and Brain\u2010Inspired Research, Shandong Provincial Key Laboratory of Brain Science Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Jinan China"},{"name":"Department of Physiology, School of Medicine Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.102944"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600933200"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478\u2010017\u20100452\u20106"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab258"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.10.017"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.0324\u201014.2014"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2014.00254"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2022.05.037"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43992"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673\u20105374.310686"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0896\u20106273(03)00568\u20103"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010316200"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201004232\u20104"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0028\u20103908(99)00006\u20104"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.08.029"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2000.7483"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.72.121801.161629"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0913572107"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.11.001"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1713969114"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1618627114"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201015813\u20108"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008\u20100993"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201600194"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3406"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13958"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.08.008"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1227157"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1090842"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkag007"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2015.12.019"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0304\u20103940(99)00463\u20102"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010021\u201000972\u2010x"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8969"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.1.390"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922287117"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5654\u201003.2004"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478\u2010024\u201001766\u20103"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010009\u20105357\u20102"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.903420302"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010019\u20100423\u20102"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.13036"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401\u2010021\u201000727\u2010z"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0896\u20106273(01)00561\u2010x"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2020.108022"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3360\u201015.2016"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.143"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.08.033"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495\u2010016\u20101218\u20105"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010020\u20100687\u20107"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105218"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010021\u201001377\u20107"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz492"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571\u2010010\u20109523\u2010y"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00381"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159x14666160119094646"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70717","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70717","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70717","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:20:03Z","timestamp":1792610403000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70717"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":56,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/acel.70717"],"URL":"https:\/\/doi.org\/10.1111\/acel.70717","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]},"assertion":[{"value":"2025-11-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70717"}}