ArticleMolecular neurodegeneration2025
sPLA2-IIA modifies progranulin deficiency phenotypes in mouse models.
Article in Molecular neurodegeneration, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundHaploinsufficiency of the progranulin (PGRN) protein is a leading cause of frontotemporal lobar degeneration (FTLD). Mouse models have been developed to study PGRN functions. However, PGRN deficiency in the commonly used C57BL/6 mouse strain background leads to very mild phenotypes, and pathways regulating PGRN deficiency phenotypes remain to be elucidated.
methodsWe generated PGRN-deficient mice in the FVB/N background and compared PGRN deficiency phenotypes between C57BL/6 and FVB/N backgrounds via immunostaining, western blot, RNA-seq, and proteomics approaches. We demonstrated a novel pathway in modifying PGRN deficiency phenotypes using inhibitor treatment and AAV-mediated overexpression in mouse models.
resultsWe report that PGRN loss in the FVB/N mouse strain results in earlier onset and stronger FTLD-related and lysosome-related phenotypes. We found that PGRN interacts with sPLA2-IIA, a member of the secreted phospholipase A2 (sPLA2) family member and a key regulator of inflammation, that is expressed in FVB/N but not C57BL/6 background. sPLA2-IIA inhibition rescues PGRN deficiency phenotypes, while sPLA2-IIA overexpression drives enhanced gliosis and lipofuscin accumulation in PGRN-deficient mice. Additionally, RNA-seq and proteomics analysis revealed that mitochondrial pathways are upregulated in the PGRN-deficient C57BL/6 mice but not in the FVB/N mice.
conclusionsOur studies establish a better mouse model for FTLD-GRN and uncover novel pathways modifying PGRN deficiency phenotypes.
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