Multi-omic analysis reveals lipid dysregulation associated with mitochondrial dysfunction in parkinson’s disease brain

Jenny Hällqvist, Christina E. Toomey, Rui Pinto, Tomas Baldwin, Ivan Doykov, Anna Wernick, Mesfer Al Shahrani, James R. Evans, Joanne Lachica, Simon Pope, Simon Heales, Simon Eaton, Kevin Mills, Sonia Gandhi and Wendy E. Heywood ()
Additional contact information
Jenny Hällqvist: UCL Great Ormond Street Institute of Child Health, Translational Mass Spectrometry Research Group, Genetic & Genomic Medicine
Christina E. Toomey: UCL Queen Square Institute of Neurology, Queen Square Brain Bank for Neurological Disorders
Rui Pinto: Imperial College London, MRC Centre for Environment and Health, School of Public Health, Department of Epidemiology and Biostatistics, Faculty of Medicine
Tomas Baldwin: UCL Great Ormond Street Institute of Child Health, Translational Mass Spectrometry Research Group, Genetic & Genomic Medicine
Ivan Doykov: UCL Great Ormond Street Institute of Child Health, Translational Mass Spectrometry Research Group, Genetic & Genomic Medicine
Anna Wernick: The Francis Crick Institute
Mesfer Al Shahrani: Queen Square & UCL Great Ormond Street Institute of Child Health, Neurometabolic Unit, National Hospital for Neurology and Neurosurgery
James R. Evans: UCL Queen Square Institute of Neurology, Department of Clinical and Movement Neurosciences
Joanne Lachica: UCL Queen Square Institute of Neurology, Department of Clinical and Movement Neurosciences
Simon Pope: Queen Square & UCL Great Ormond Street Institute of Child Health, Neurometabolic Unit, National Hospital for Neurology and Neurosurgery
Simon Heales: Queen Square & UCL Great Ormond Street Institute of Child Health, Neurometabolic Unit, National Hospital for Neurology and Neurosurgery
Simon Eaton: Developmental Biology and Cancer University College London Great Ormond Street Institute of Child Health
Kevin Mills: UCL Great Ormond Street Institute of Child Health, Translational Mass Spectrometry Research Group, Genetic & Genomic Medicine
Sonia Gandhi: UCL Queen Square Institute of Neurology, Department of Clinical and Movement Neurosciences
Wendy E. Heywood: UCL Great Ormond Street Institute of Child Health, Translational Mass Spectrometry Research Group, Genetic & Genomic Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Parkinson’s disease (PD) is an increasingly prevalent neurodegenerative disorder, largely sporadic in origin, with limited understanding of age- and region-specific lipid alterations in the human brain. Dysregulation of glycosphingolipid catabolism has been implicated in PD, yet comprehensive spatiotemporal profiling remains sparse. Here, we performed targeted lipidomics across eight anatomically distinct brain regions in post-mortem controls, mid-stage, and late-stage PD cases using high-precision tissue dissection. Each region displayed distinct lipid signatures, with several age-associated alterations—most notably in hexosylceramides, including glucosylceramide. In PD, glycosphingolipids were reduced in subcortical regions but elevated in cortical regions, particularly gangliosides, HexCer, and Hex2Cer, accompanied by increased sphingolipids and decreased phospholipids. The most pronounced mid-stage changes occurred in the putamen, where very long chain ceramide species and plasmalogen PE decreased, then normalising in late-stage disease. Lyso-phosphatidylcholine increased progressively throughout PD progression. Integrating proteomic data, we observed sphingomyelin levels associated with PD-related proteins, while dysregulated mitochondrial function correlated with antioxidant plasmalogens, long-chain ceramides, lyso-phosphatidylcholine, and HexCer in the putamen. These findings highlight region- and stage-specific lipid alterations in PD and their potential convergence with mitochondrial dysfunction.

Date: 2025
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DOI: 10.1038/s41467-025-65489-2

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