Cell type-specific lipid storage changes in Parkinson’s disease patient brains are recapitulated by experimental glycolipid disturbance

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-11, Vol.117 (44), p.27646-27654
• Main Authors: Brekk, Oeystein Roed, Honey, Jonathan R., Lee, Seungil, Hallett, Penelope J., Isacson, Ole
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; alpha-Synuclein - metabolism; Animals; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Biological Sciences; Case-Control Studies; Central nervous system; Cohort Studies; Disease Models, Animal; Dopamine receptors; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Female; Fluorescent indicators; Glucosylceramidase; Glucosylceramidase - genetics; Glucosylceramidase - metabolism; Glycolipids - metabolism; Glycoproteins; Healthy Volunteers; Homeostasis; Humans; Inflammation; Lipids; Localization; Male; Melanoma; Membrane Glycoproteins - metabolism; Mesencephalon; Metabolites; Metastases; Mice; Microglia; Microglia - metabolism; Microglia - pathology; Middle Aged; Movement disorders; Neurodegenerative diseases; Neuronal-glial interactions; Neurons; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Protein B; Signaling; Substantia nigra; Substantia Nigra - cytology; Substantia Nigra - metabolism; Substantia Nigra - pathology; Triglycerides; Triglycerides - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2003021117

Neurons are dependent on proper trafficking of lipids to neighboring glia for lipid exchange and disposal of potentially lipotoxic metabolites, producing distinct lipid distribution profiles among various cell types of the central nervous system. Little is known of the cellular distribution of neutral lipids in the substantia nigra (SN) of Parkinson’s disease (PD) patients and its relationship to inflammatory signaling. This study aimed to determine human PD SN neutral lipid content and distribution in dopaminergic neurons, astrocytes, and microglia relative to age-matched healthy subject controls. The results show that while total neutral lipid content was unchanged relative to age-matched controls, the levels of whole SN triglycerides were correlated with inflammationattenuating glycoprotein non-metastatic melanoma protein B (GPNMB) signaling in human PD SN. Histological localization of neutral lipids using a fluorescent probe (BODIPY) revealed that dopaminergic neurons and midbrain microglia significantly accumulated intracellular lipids in PD SN, while adjacent astrocytes had a reduced lipid load overall. This pattern was recapitulated by experimental in vivo inhibition of glucocerebrosidase activity in mice. Agents or therapies that restore lipid homeostasis among neurons, astrocytes, and microglia could potentially correct PD pathogenesis and disease progression.