Shi Yiyue, Hou Wenyu, Li Bei, Zhu Caihong
School of Basic Medical Sciences, Fudan University, Shanghai, China.
Shanghai Key Laboratory for Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China.
Commun Biol. 2025 Jun 2;8(1):844. doi: 10.1038/s42003-025-08272-9.
Dysregulated lipid metabolism in microglia represents a hallmark of neuroinflammation and is often observed in a variety of neurodegenerative diseases. The exact molecular mechanisms underlying the induction of altered lipid homeostasis and how it contributes to neurodegeneration remain to be deciphered. Progranulin (PGRN) is a lysosomal glycoprotein encoded by GRN. Loss-of-function mutations or variants of GRN have been linked to various neurodegenerative diseases. PGRN has recently been identified as a regulator of lipid droplet formation in microglia. Additionally, PGRN has been reported to interact with various molecules to modulate lysosomal lipid metabolism, including glycerolipids and sphingolipids in neurons. Hence, PGRN deficiency-mediated lipid dysregulation may represent a significant contributing factor to the neuroinflammation and the pathogenesis of related neurodegenerative diseases. Understanding how PGRN regulates lipid metabolism is crucial for developing therapeutic strategies to restore lipid homeostasis in microglia and mitigate neuroinflammation, thus offering hope for effective treatments to combat these neurodegenerative disorders in the future.
小胶质细胞中脂质代谢失调是神经炎症的一个标志，并且在多种神经退行性疾病中经常观察到。脂质稳态改变的诱导背后的确切分子机制以及它如何导致神经退行性变仍有待阐明。前颗粒蛋白（PGRN）是一种由GRN编码的溶酶体糖蛋白。GRN的功能丧失突变或变异与各种神经退行性疾病有关。PGRN最近被确定为小胶质细胞中脂滴形成的调节因子。此外，据报道PGRN与各种分子相互作用以调节溶酶体脂质代谢，包括神经元中的甘油脂质和鞘脂。因此，PGRN缺乏介导的脂质失调可能是神经炎症和相关神经退行性疾病发病机制的一个重要促成因素。了解PGRN如何调节脂质代谢对于制定恢复小胶质细胞脂质稳态和减轻神经炎症的治疗策略至关重要，从而为未来对抗这些神经退行性疾病的有效治疗带来希望。
