Progranulin promotes dendritic growth of hippocampal neurons by acting on astrocytes

ABSTRACT: Progranulin is a secreted pro-protein that is trafficked to lysosomes and exerts protective effects in the brain. Progranulin (GRN) mutations, most of which cause progranulin haploinsufficiency, are a major genetic cause of frontotemporal dementia (FTD). Restoring progranulin to people with GRN mutations is a promising treatment strategy, but understanding progranulin’s mechanism of action may enable design of optimal progranulin-based therapies. Progranulin restrains inflammation and promotes neuronal growth and survival, but the mechanisms underlying these effects are unclear. Progranulin is constitutively secreted and interacts with various signaling receptors, but is also taken up and trafficked to lysosomes, where it is necessary for maintaining normal lysosomal function. In previous work, we showed that progranulin acts in lysosomes to promote neuronal survival, but it is not clear if progranulin enhances neuronal growth by acting in lysosomes or through extracellular signaling. To address this question, we employed lentiviral vectors expressing either progranulin (PGRN) or a non-secreted, lysosome-targeted progranulin (L-PGRN). Using lentiviral vectors driven by non-selective (PGK), neuron-selective (hSyn), or astrocyte-selective (GFAP) promoters, we found that delivering L-PGRN to astrocytes, but not neurons, promoted dendritic outgrowth in primary hippocampal cultures. Using transwell co-cultures of astrocytes and neurons, we found that neurons cultured with L-PGRN–transduced astrocytes had greater dendritic outgrowth than those cultured with GFP-transduced astrocytes. Bulk RNA sequencing of primary astrocytes indicated that L-PGRN reduced transcriptomic pathways associated with inflammation and cellular reactivity. Consistent with this result, we found that reducing the number of astrocytes in hippocampal cultures increased dendritic outgrowth and occluded the pro-growth effects of L-PGRN. These data show that under these culture conditions, progranulin secretion is not required to promote dendritic outgrowth. Instead, progranulin may act via a non-cell–autonomous mechanism to suppress secretion of factors from astrocytes that restrain neuronal growth. These data add to a growing body of evidence that progranulin can act on astrocytes to promote neuronal health.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE302849 | GEO | 2025/11/03

REPOSITORIES: GEO