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TL;DR
This study used cell and animal models to show that cholestanol, a molecule elevated in some Parkinson's disease patients, activates a protease called AEP, which in turn promotes the aggregation and spreading of α-synuclein pathology.
JCI Insight · 14 authors, 7 centres
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This study used cell and animal models to show that cholestanol, a molecule elevated in some Parkinson's disease patients, activates a protease called AEP, which in turn promotes the aggregation and spreading of α-synuclein pathology.
The study investigates the link between cholestanol, a hallmark of the genetic disorder CTX, and sporadic Parkinson's disease (PD). Researchers found serum cholestanol levels were higher in sporadic PD patients compared to controls. Using cell cultures and a mouse model where α-synuclein fibrils were injected into the striatum, they demonstrated that cholestanol activates the C/EBPβ/AEP pathway. This activation leads to the cleavage and aggregation of α-synuclein, promotes its spreading, and causes degeneration of the nigrostriatal dopaminergic pathway, resulting in PD-like motor symptoms. Genetic knockout of AEP or administration of an AEP inhibitor (CP11) mitigated these pathological changes.