Abstract
<title>Abstract</title> <p> Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and the pathological accumulation of α-synuclein (αSyn) aggregates to Lewy bodies (LBs). While LB formation is a hallmark of PD, the molecular mechanisms underlying αSyn aggregation remain incompletely defined. We recently identified an early loss of fragile X mental retardation protein (FMRP) in dopaminergic neurons in PD, although the downstream consequences of FMRP loss were previously unclear. Here, we reveal a novel connection between FMRP and insulin-related signaling in the nigrostriatal system. Proteomic analysis of FMRP knockout (KO) mice uncovered an upregulation of insulin-degrading enzyme (IDE), a Zn-metalloprotease involved in metabolic regulation and amyloid clearance. Increased IDE expression was confirmed in both FMRP KO mice and human fragile X syndrome (FXS) brain tissue, indicating conserved FMRP-dependent regulation of IDE across species. Functional assays in Lund Human Mesencephalic (LUHMES) cells demonstrated that IDE interacts with αSyn and influences its aggregation state: IDE overexpression reduced αSyn aggregation, while IDE knockdown enhanced fibrillar αSyn accumulation and associated cytotoxicity. Consistently, pharmacological inhibition of IDE increased αSyn aggregation in human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons lacking DJ-1 ( <italic>PARK7</italic> ), indicating that distinct PD-relevant genetic perturbations converge on this pathway. In vivo, IDE deficiency exacerbated αSyn pathology in mice injected with preformed αSyn fibrils. Furthermore, IDE was upregulated in αSyn-overexpressing mice and in postmortem brains from individuals with incidental Lewy body disease – a presumed pathological precursor – and PD. Together, these findings identify IDE as a novel modulator of αSyn solubility and aggregation dynamics and suggest that FMRP-mediated control of IDE expression may modulate early pathogenic events in PD. </p>