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

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.