Denali Therapeutics, South San Francisco, CA, USA.
Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; On behalf of the ALLFTD investigators.
Cell. 2021 Sep 2;184(18):4651-4668.e25. doi: 10.1016/j.cell.2021.08.002. Epub 2021 Aug 26.
GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.
GRN 突变导致颗粒体蛋白前体基因（GRN）功能缺失，从而引发额颞叶痴呆（GRN-FTD）。颗粒体蛋白前体（PGRN）是一种溶酶体分泌蛋白，其功能尚不清楚。在这里，我们发现 Grn 小鼠表现出双（单酰基甘油）磷酸（BMP）的全身性缺乏，BMP 是我们鉴定出的一种内溶酶体磷脂，它是一种 pH 依赖性的 PGRN 相互作用物，也是溶酶体蛋白水解和脂肪分解的氧化还原敏感增强剂。Grn 大脑还显示出葡萄糖脑苷脂酶底物葡萄糖神经酰胺的年龄依赖性二次储存。我们通过工程蛋白转运载体（PTV）：PGRN 研究了一种蛋白替代策略：将 PGRN 与一种改良的 Fc 结构域连接的重组蛋白，该结构域与人类转铁蛋白受体结合，以增强中枢神经系统的生物分布。PTV：PGRN 挽救了原代小鼠巨噬细胞和人诱导多能干细胞衍生的小神经胶质细胞中的各种 Grn 表型，包括氧化应激、溶酶体功能障碍和内膜损伤。外周递送的 PTV：PGRN 纠正了 Grn 中枢神经系统中 BMP、葡萄糖神经酰胺和疾病病理学的水平，包括小神经胶质细胞增生、脂褐素沉积和神经元损伤。因此，PTV：PGRN 代表了一种治疗 GRN-FTD 的潜在生物疗法。
