When glia turn toxic: progranulin deficiency as a driver of neuronal damage

Glial cells are central regulators of brain homeostasis, and their dysfunction is increasingly implicated in neurodegenerative diseases. Loss-of-function mutations in granulin (GRN), leading to progranulin (PGRN) deficiency, disrupt immune regulation, cellular clearance, and neuronal integrity. Reduced PGRN levels are implicated in a spectrum of neurodegenerative disorders and are also observed during aging. To dissect PGRN-dependent mechanisms, we established a disease-relevant cellular model by generating GRN-KO glial cells and assessed non-cell-autonomous effects on wild-type mature SH-SY5Y neurons exposed to PGRN-deficient glial conditioned medium. These progranulin-deficient glial cells exhibited a disease-like phenotype characterized by impaired phagocytic capacity, an altered inflammatory profile, and a senescence-like state associated with reduced motility, highlighting a critical role for PGRN in glial homeostasis. Wild-type neurons treated with glia-derived conditioned medium displayed structural and functional deficits, including synaptic instability and reduced dendritic complexity, as revealed by optical and confocal microscopy, indicating that PGRN-deficient glia release factors detrimental to neuronal integrity. Exposure to environmental and inflammatory stressors further exacerbated glial dysfunction, consistently amplifying GRN-KO-associated phenotypes. Taken together, these findings establish glial PGRN deficiency as a primary driver of non-cell-autonomous neuronal vulnerability and validate this glial model as a robust platform for mechanistic investigation. Finally, we highlight rescue strategies targeting PGRN-related pathways, including granulin-derived peptides and natural bioactive compounds, as promising approaches to restore cellular homeostasis and mitigate disease-associated phenotypes.