MEK1/2 inhibitors suppress pathological α-synuclein and neurotoxicity in cell models and a humanized mouse model of Parkinson’s disease

作者：Huilan Wang, Qing Wang, Haoxiang Xu, Yuanzheng Wu, S. Cheung, Qianhui Xu, Chengfang Pan, Jingyu Cao, Zhiyuan Cao, Ruonan Yang, Yu Ding, Yiyan Fei, Yongfeng Chen, Jian Wang, Cong Liu, Boxun Lu · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.adp4625 · 被引用次数：7 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Nuclear Receptors and Signaling、Neurological diseases and metabolism

The abnormal accumulation of misfolded proteins is a common hallmark of many neurodegenerative disorders. Among these proteins, α-synuclein (αsyn) is a well-characterized pathogenic protein in Parkinson’s disease (PD) and other synucleinopathies. αsyn can be hyperphosphorylated and form pathological aggregates, leading to neurodegeneration. Thus, chemical modulators of pathological αsyn 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 αsyn in wild-type cells and that pathological αsyn in αsyn preformed fibrils (αsyn-PFF) induced the neuroblastoma cell line SHSY-5Y, PC12 cells, and primary cultured neurons. We further demonstrated that these inhibitors suppressed Ser 129 phosphorylated αsyn (p-αsyn) through the kinase PLK2 downstream of MEK1/2-ERK2 in PD cell models. We established a humanized PD mouse model by injecting human αsyn-PFF into mice with homozygous knock-in of human SNCA . Oral administration of blood-brain barrier–penetrable MEK1/2 inhibitors lowered pathological αsyn 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.