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sPLA2-IIA modifies progranulin deficiency phenotypes in mouse models
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sPLA2-IIA modifies progranulin deficiency phenotypes in mouse models
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sPLA2-IIA modifies progranulin deficiency phenotypes in mouse models
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Journal Article
sPLA2-IIA modifies progranulin deficiency phenotypes in mouse models
2025
Overview
Background
Haploinsufficiency 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.
Methods
We 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.
Results
We 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.
Conclusions
Our studies establish a better mouse model for FTLD-
GRN
and uncover novel pathways modifying PGRN deficiency phenotypes.
Publisher
BioMed Central,BioMed Central Ltd,BMC
