biostudies-literatureLee EBio & Medical Technology Development Program of the NRFNational Research Council of Science & Technology (NST) grantBio & Medical Technology Development Program of the NRFNational Research Council of Science & Technology (NST) grantKorea Health Technology R&D Project through the Korea Health Industry Development InstituteKorea Health Technology R&D Project through the Korea Health Industry Development InstituteKorea Basic Science Institute (National research Facilities and Equipment Center) grantKorean ARPA-H Project through the Korea Health Industry Development Institute49https://www.ebi.ac.uk/biostudies/studies/S-EPMC12910077biostudies-literatureUnknown12(1)Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-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 α-synuclein transgenic mouse model, primary neurons from patients with PD, and patient-derived midbrain organoids. We found that inhibiting de novo ceramide biosynthesisNPJ Parkinson's diseaseInhibition of de novo ceramide synthesis mitigates alpha-synuclein pathology in a Parkinson's disease mouse model.PMC12910077RS-2024-00440824RS-2024-005072562023R1A6C101A045CAP23021-000RS-2024-00439685Park MYHwang NPark MWei SOh CMKim NYRyu HLee GRyu DPark DLee EfalseInhibition of de novo ceramide synthesis mitigates alpha-synuclein pathology in a Parkinson's disease mouse model.Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-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 α-synuclein transgenic mouse model, primary neurons from patients with PD, and patient-derived midbrain organoids. We found that inhibiting de novo ceramide biosynthesis2026-01-01T00:00:00Z2026 Jan2026-07-16T05:04:01.901Z2026-07-09T10:37:02.219ZS-EPMC129100774155906210.1038/s41531-026-01263-5