Inhibition of de novo ceramide synthesis mitigates alpha-synuclein pathology in a Parkinson's disease mouse model

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of alpha-synuclein aggregates. Ceramide metabolism is increasingly implicated in protein aggregation and mitochondrial dysfunction, both of which are prevalent in neurodegenerative disorders. While prior studies using cell lines have hinted at ceramide's role in PD, the in vivo relevance and therapeutic efficacy of inhibiting its synthesis remained largely unexplored. We aimed to evaluate the therapeutic potential of inhibiting ceramide synthesis in various models of PD, including the A53T alpha-synuclein transgenic mouse model, primary neurons from patients with PD, and patient-derived midbrain organoids. We found that inhibiting de novo ceramide biosynthesis decreases alpha-synuclein aggregation and improves motor and cognitive function in A53T alpha-synuclein transgenic mice. Treatment with myriocin, a serine palmitoyltransferase inhibitor, restored mitochondrial morphology, enhanced mitophagy, and reduced neuroinflammation. Single-nucleus transcriptomic analysis revealed that myriocin normalized gene networks related to synaptic transmission, mitochondrial homeostasis, and inflammation. Additionally, human midbrain organoids derived from PD patient-induced pluripotent stem cells exhibited reduced alpha-synuclein aggregation and preserved dopaminergic neurons following myriocin treatment. Together, these results suggest that targeting ceramide synthesis is a promising strategy for addressing protein aggregation and neuronal death in PD.