Grn-flox Mouse

Grn, encoding progranulin (PGRN), is a gene of great significance. PGRN is a lysosomal and secreted protein involved in regulating lysosomal biogenesis, inflammation, repair, stress response, and aging, playing a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain [2].

Grn -/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid that interacts with PGRN in a pH-dependent manner and enhances lysosomal proteolysis and lipolysis. These mice also show an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine [1]. Peripherally delivered PTV:PGRN, a recombinant protein, can rescue various Grn -/- phenotypes in primary murine macrophages and human iPSC-derived microglia, and correct levels of BMP, glucosylsphingosine, and disease pathology in Grn -/- CNS, including microgliosis, lipofuscinosis, and neuronal damage [1].

In conclusion, Grn is essential for normal lysosomal function and maintaining the health of the central nervous system. The study of Grn -/- mouse models has revealed its role in neurodegenerative diseases such as frontotemporal dementia (FTD), suggesting that restoring PGRN levels could be a potential therapeutic strategy for FTD-GRN [1,2].