Fig. 8: Schematic summary of mechanism underlying the neuroprotective effects of IDE in PD.

Based on our findings, IDE exerts anti-PD effects by inhibiting the Hippo signaling pathway via MST1/2 targets. In the normal state, the constitutively expressed IDE inhibited the decline of p-MST1/2, p-Mob1b, and p-YAP, along with the decline of MST1/2, Mob1b, and the induction of YAP (precluded from the degradation of phosphorylated proteins), maintaining the homeostasis of the Hippo signaling pathways. Thereby, IDE decreased the assembly of α-syn and the neurotoxicity by apoptosis of the IDE-Hippo axis (left panel). In contrast, under pathological conditions of PD, decreased IDE levels lost the ability to cope well with intracellular stress, and the dysregulated Hippo signaling pathways increased the p-MST1/2, p-Mob1b, and p-YAP, along with the increase of MST1/2 and Mob1b, and lowered the YAP levels. Jointly, the series of alterations finally aggravated the accumulation of α-syn and the neuronal apoptosis via increasing Bax and Caspase 3 level, and decreasing the level of Bcl-2, leading to the progression of PD (right panel).