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

Significance

Recently, the field of Parkinson’s disease biology has shifted attention away from pure proteinotoxic hypotheses to emphasize primary cellular insults, including glycolipid disturbances. In this work, dopaminergic neurons in the Parkinson’s disease-vulnerable region of substantia nigra were found to accumulate neutral lipids, whereas in the same tissues, astrocytes have reduced lipid content, and resident microglia (a form of brain macrophage) show overall accumulation of lipids associated with inflammation. These changes were reproduced experimentally by blocking a specific lysosomal hydrolase in mice, generating a glycolipid accumulation in the animals. Based on these findings, it is reasonable to propose that restoring lipid homeostasis between neurons, astrocytes, and microglia could potentially influence PD pathogenesis and disease progression.

Abstract

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 inflammation-attenuating 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.