Insulin-degrading enzyme confers neuroprotection in Parkinson’s disease by inhibiting the Hippo signaling pathway

作者：Huimin Zheng, Yuming Guo, Shuyu Zhang, Yun Su, Xin Cui, Zhengwei Hu, Xiaoyan Hao, Mengjie Li, Changhe Shi, Yuming Xu, Chengyuan Mao · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-08055-4 · 被引用次数：3 · 研究领域：Hippo pathway signaling and YAP/TAZ、Parkinson's Disease Mechanisms and Treatments、Wnt/β-catenin signaling in development and cancer

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily marked by the degeneration of dopaminergic neurons and pathological α-synuclein (α-syn) accumulation. Although insulin-degrading enzyme (IDE) has been implicated in both type 2 diabetes mellitus and amyloid-protein clearance, its precise relevance to PD pathogenesis remains unclear. In this study, we show that IDE expression is reduced in the nigrostriatal region of aging homozygous A53T α-syn mice and in α-syn-overexpressing SH-SY5Y PD cells. Overexpression of IDE alleviated motor deficits, reduced pathological α-syn levels, and protected dopaminergic neurons in A53T α-syn mice. In SH-SY5Y PD model cells, IDE overexpression reduced α-syn-induced toxicity, whereas IDE knockdown exacerbated it. Integrated transcriptomic and proteomic analyses revealed that the Hippo signaling pathway serves as a major downstream target of IDE. Notably, inhibition of MST1/2, a pivotal Hippo kinase, recapitulated IDE's neuroprotective effects by diminishing α-syn pathology and neuronal apoptosis. Hence, IDE confers neuroprotection partly via suppression of the Hippo signaling pathway, and pharmacological targeting of the IDE-Hippo axis may represent a promising therapeutic strategy for PD.