Neuroregeneration Institute, McLean Hospital/Departments of Neurology and Psychiatry, Harvard Medical School, Belmont, MA 02478
Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478.
Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27646-27654. doi: 10.1073/pnas.2003021117. Epub 2020 Oct 15.
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.
神经元依赖于脂质的正确转运，以便与邻近的神经胶质细胞进行脂质交换和潜在脂毒性代谢产物的处理，从而在中枢神经系统的各种细胞类型中产生不同的脂质分布特征。目前对于帕金森病（PD）患者黑质（SN）中的中性脂质的细胞分布及其与炎症信号的关系知之甚少。本研究旨在确定帕金森病患者 SN 中多巴胺能神经元、星形胶质细胞和小胶质细胞中性脂质的含量和分布，与年龄匹配的健康对照进行比较。结果表明，虽然相对于年龄匹配的对照组，总中性脂质含量没有变化，但整个 SN 甘油三酯的水平与帕金森病患者 SN 中炎症减弱的糖蛋白非转移性黑色素瘤蛋白 B（GPNMB）信号相关。使用荧光探针（BODIPY）对中性脂质进行组织学定位显示，多巴胺能神经元和中脑小胶质细胞在 PD SN 中显著积累了细胞内脂质，而相邻的星形胶质细胞总体脂质负荷降低。这一模式在小鼠体内抑制葡糖脑苷脂酶活性的实验中得到了重现。恢复神经元、星形胶质细胞和小胶质细胞之间脂质动态平衡的药物或治疗方法可能有助于纠正 PD 的发病机制和疾病进展。
