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Delivering Progranulin to Astrocytic Lysosomes Promotes Growth of Co-Cultured Neurons

  • 0Killion Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Journal of Neurochemistry +

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November 3, 2025

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November 3, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Restoring progranulin (PGRN) in astrocytes, not neurons, promotes neuronal growth by acting within astrocytic lysosomes. This mechanism involves reducing factors that inhibit neuronal outgrowth, offering new therapeutic insights for frontotemporal dementia (FTD).

Area Of Science

  • Neuroscience
  • Genetics
  • Cell Biology

Background

  • Progranulin (GRN) mutations are a leading genetic cause of frontotemporal dementia (FTD), often resulting in progranulin haploinsufficiency.
  • Progranulin's role in neuronal survival and growth is not fully understood, with potential mechanisms involving extracellular signaling or lysosomal function.
  • Previous research indicated progranulin acts within neuronal lysosomes to promote survival.

Purpose Of The Study

  • To investigate the mechanism by which progranulin (PGRN) promotes neuronal growth.
  • To determine if progranulin's effects on neuronal growth are mediated by extracellular signaling or lysosomal action.
  • To explore the potential of targeting astrocytic lysosomes for therapeutic interventions in FTD.

Main Methods

  • Utilized lentiviral vectors to express progranulin (PGRN) or a lysosome-targeted version (L-PGRN) in primary rat hippocampal neurons and astrocytes.
  • Employed neuron-selective (hSyn) and astrocyte-selective (GFAP) promoters to control gene expression.
  • Conducted RNA sequencing on astrocytes and analyzed astrocyte-conditioned medium; performed co-culture experiments and astrocyte depletion assays.

Main Results

  • Delivery of L-PGRN to astrocytes, but not neurons, significantly promoted dendritic outgrowth in hippocampal neurons.
  • L-PGRN-transduced astrocytes reduced the secretion of PAI-1, a known inhibitor of neuronal outgrowth.
  • Astrocyte depletion increased dendritic outgrowth, suggesting astrocytes normally restrain neuronal growth, and this effect was occluded by L-PGRN.

Conclusions

  • Progranulin promotes neuronal growth through a non-cell autonomous mechanism involving its action within astrocytic lysosomes.
  • Targeting astrocytic lysosomes with progranulin may counteract inhibitory factors secreted by astrocytes, thereby enhancing neuronal outgrowth.
  • These findings support a model where progranulin acts on astrocytes to promote neuronal health, offering a potential therapeutic strategy for FTD.

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