Yang Cha, Du Huan, Lee Gwang Bin, Uematsu Masaaki, He Weiguo, Doré Etienne, Yu Weizhi, Sanford Ethan J, Smolka Marcus B, Boilard Eric, Baskin Jeremy M, Hao Ling, Hu Fenghua
Department of Molecular Biology and Genetics, 345 Weill Hall, Ithaca, NY, 14853, USA.
Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, 14853, USA.
Mol Neurodegener. 2025 Jun 17;20(1):72. doi: 10.1186/s13024-025-00863-8.
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.
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.
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.
Our studies establish a better mouse model for FTLD-GRN and uncover novel pathways modifying PGRN deficiency phenotypes.
前颗粒蛋白（PGRN）单倍剂量不足是额颞叶痴呆（FTLD）的主要病因。已建立小鼠模型来研究PGRN的功能。然而，在常用的C57BL/6小鼠品系背景中PGRN缺乏导致非常轻微的表型，调节PGRN缺乏表型的途径仍有待阐明。
我们在FVB/N背景中生成了PGRN缺陷小鼠，并通过免疫染色、蛋白质印迹、RNA测序和蛋白质组学方法比较了C57BL/6和FVB/N背景之间的PGRN缺乏表型。我们在小鼠模型中使用抑制剂处理和腺相关病毒介导的过表达证明了一种改变PGRN缺乏表型的新途径。
我们报告FVB/N小鼠品系中PGRN缺失导致更早发病和更强的FTLD相关及溶酶体相关表型。我们发现PGRN与分泌型磷脂酶A2（sPLA2）家族成员sPLA2-IIA相互作用，sPLA2-IIA是炎症的关键调节因子，在FVB/N背景中表达而在C57BL/6背景中不表达。抑制sPLA2-IIA可挽救PGRN缺乏表型，而sPLA2-IIA过表达会导致PGRN缺陷小鼠中胶质增生和脂褐素积累增强。此外，RNA测序和蛋白质组学分析显示，PGRN缺陷的C57BL/6小鼠中线粒体途径上调，而FVB/N小鼠中则不然。
我们的研究建立了一个更好的FTLD-GRN小鼠模型，并发现了改变PGRN缺乏表型的新途径。
