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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月24日

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  • Huimin Zheng,
  • Yu Guo,
  • Shuyu Zhang,
  • Yun Su,
  • Xin Cui,
  • Zhengwei Hu,
  • Xiaoyan Hao,
  • Mengjie Li,
  • Changhe Shi,
  • Yuming Xu,
  • Chengyuan Mao

摘要

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.