{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:14:17Z","timestamp":1790892857491,"version":"4.1.0"},"reference-count":66,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"798","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,5,14]]},"abstract":"<jats:p>\n                    The abnormal accumulation of misfolded proteins is a common hallmark of many neurodegenerative disorders. Among these proteins, \u03b1-synuclein (\u03b1syn) is a well-characterized pathogenic protein in Parkinson\u2019s disease (PD) and other synucleinopathies. \u03b1syn can be hyperphosphorylated and form pathological aggregates, leading to neurodegeneration. Thus, chemical modulators of pathological \u03b1syn may suppress its downstream toxicity and provide entry points to therapeutic intervention. Here, we identified mitogen-activated protein kinase kinase 1\/2 (MEK1\/2) inhibitors as negative modulators of basal \u03b1syn in wild-type cells and that pathological \u03b1syn in \u03b1syn preformed fibrils (\u03b1syn-PFF) induced the neuroblastoma cell line SHSY-5Y, PC12 cells, and primary cultured neurons. We further demonstrated that these inhibitors suppressed Ser\n                    <jats:sup>129<\/jats:sup>\n                    phosphorylated \u03b1syn (p-\u03b1syn) through the kinase PLK2 downstream of MEK1\/2-ERK2 in PD cell models. We established a humanized PD mouse model by injecting human \u03b1syn-PFF into mice with homozygous knock-in of human\n                    <jats:italic toggle=\"yes\">SNCA<\/jats:italic>\n                    . Oral administration of blood-brain barrier\u2013penetrable MEK1\/2 inhibitors lowered pathological \u03b1syn and rescued PD-relevant phenotypes with an acceptable safety profile in these mice. Collectively, these data highlight MEK1\/2 inhibitors as a potential therapeutic strategy for PD.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adp4625","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T13:58:37Z","timestamp":1747231117000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["MEK1\/2 inhibitors suppress pathological \u03b1-synuclein and neurotoxicity in cell models and a humanized mouse model of Parkinson\u2019s disease"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4452-489X","authenticated-orcid":true,"given":"Huilan","family":"Wang","sequence":"first","affiliation":[{"name":"Neurology Department at Huashan Hospital, School of Life Sciences, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai 200438, China."},{"name":"New 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