Related Experiment Video
Updated: Jan 15, 2026
Establishment of a Surgically-induced Model in Mice to Investigate the Protective Role of Progranulin in Osteoarthritis
Published on: February 25, 2014
Ablation of progranulin augments microglial activation and accelerates prion progression
Bei Li1, Yiyue Shi1, Wenyu Hou1
1School of Basic Medical Sciences, State Key Laboratory of Brain Function and Disorders, Fudan University, Dong'An Rd 130, Shanghai, 200032, China.
Abstract:
Mutations or polymorphisms in GRN, encoding the CNS glycoprotein progranulin (PGRN), have been linked to several neurodegenerative diseases. In this study, we explored the role of PGRN in prion diseases. We observed that prion infection upregulated microglial PGRN expression. Following intracerebral inoculation with RML6 prions, Grn-/- mice exhibited accelerated disease progression compared to Grn+/- and Grn+/+ littermates. Histological analysis revealed augmented microglial activation in Grn-/- mice. Temporal analysis revealed enhanced early microglial activation and prion clearance at 120 dpi, followed by excessive complement activation but inadequate clearance by 150 dpi. Additionally, Grn-/- brains exhibited exacerbated astrogliosis and vacuolation. RNA-seq analysis indicated that complete PGRN deficiency in prion-infected mice shifted microglia from homeostatic to pro-inflammatory states. Notably, microglia-specific depletion of PGRN did not affect prion pathogenesis, suggesting that PGRN deficiency affects microglial activation and prion progression in a non-cell autonomous manner. These findings suggest that microglia respond to prion infection in a stepwise manner, and PGRN plays a critical role in modulating prion-induced microglial activation. Our results highlight the neuroprotective role of PGRN in prion disease and suggest that supplementation or boosting expression of PGRN could represent a promising therapeutic strategy.
Insights
Progranulin (PGRN) deficiency accelerates prion disease by promoting harmful microglial activation. Boosting PGRN may offer a neuroprotective therapy for prion and other neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Mutations in GRN, encoding progranulin (PGRN), are linked to neurodegenerative diseases.
- Progranulin's role in prion diseases remains largely unexplored.
Purpose of the Study:
- To investigate the function of PGRN in prion disease pathogenesis.
- To determine the impact of PGRN deficiency on microglial responses to prion infection.
Main Methods:
- Utilized Grn knockout (Grn-/-) and wild-type mice inoculated with prions.
- Performed histological analysis, temporal profiling, and RNA-sequencing.
- Investigated microglia-specific PGRN depletion.
Main Results:
- Grn-/- mice showed accelerated prion disease progression and increased microglial activation.
- Complete PGRN deficiency shifted microglia to a pro-inflammatory state.
- PGRN deficiency impacted prion clearance and exacerbated neuropathology.
- Microglia-specific PGRN depletion did not alter prion pathogenesis, indicating non-cell autonomous effects.
Conclusions:
- Progranulin (PGRN) plays a critical neuroprotective role in prion disease.
- PGRN modulates prion-induced microglial activation and disease progression.
- Therapeutic strategies targeting PGRN may be beneficial for prion diseases.
