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.

神经元依赖于脂质向邻近神经胶质的适当运输，以进行脂质交换和潜在的脂毒性代谢物的处置，从而在中枢神经系统的各种细胞类型之间产生不同的脂质分布特征。关于帕金森病（PD）患者黑质（SN）中中性脂质的细胞分布及其与炎症信号的关系知之甚少。这项研究旨在确定与年龄匹配的健康受试者对照相比，人多巴胺能神经元，星形胶质细胞和小胶质细胞中人PD SN中性脂质的含量和分布。结果显示，尽管总中性脂质含量相对于年龄匹配的对照组没有变化，整个SN甘油三酸酯的水平与人PD SN中的炎症减轻糖蛋白非转移性黑色素瘤蛋白B（GPNMB）信号传导相关。使用荧光探针（BODIPY）对中性脂质的组织学定位显示，多巴胺能神经元和中脑小胶质细胞显着积累了PD SN中的细胞内脂质，而相邻的星形胶质细胞总体上降低了脂质负荷。通过实验性体内抑制小鼠中的葡萄糖脑苷脂酶活性来概括这种模式。恢复神经元，星形胶质细胞和小胶质细胞之间脂质稳态的药物或疗法可能会纠正PD的发病机理和疾病进展。使用荧光探针（BODIPY）对中性脂质的组织学定位显示，多巴胺能神经元和中脑小胶质细胞显着积累了PD SN中的细胞内脂质，而相邻的星形胶质细胞总体上降低了脂质负荷。通过实验性体内抑制小鼠中的葡萄糖脑苷脂酶活性来概括这种模式。恢复神经元，星形胶质细胞和小胶质细胞之间脂质稳态的药物或疗法可能会纠正PD的发病机理和疾病进展。使用荧光探针（BODIPY）对中性脂质的组织学定位显示，多巴胺能神经元和中脑小胶质细胞显着积累了PD SN中的细胞内脂质，而相邻的星形胶质细胞总体上降低了脂质负荷。通过实验性体内抑制小鼠中的葡萄糖脑苷脂酶活性来概括这种模式。恢复神经元，星形胶质细胞和小胶质细胞之间脂质稳态的药物或疗法可能会纠正PD的发病机理和疾病进展。