Fig. 1: Association of GRN genotype and PGRN dosage with various neurodegenerative diseases.

Haploinsufficiency of PGRN caused by heterozygous GRN mutations almost always leads to FTD, whereas homozygous mutation of GRN causes NCL. Additionally, variants in GRN are linked to a high risk of developing AD, PD and ALS. Under physiological conditions, PGRN is located in lysosomes and plays important roles in keeping microglia homeostatic, promoting neuronal survival, regulating lysosomal functions and maintaining lipid homeostasis. However, deficiency of PGRN often results in neuroinflammation, neuronal loss, lysosomal dysfunction and dysregulated lipid metabolism, leading to neurodegeneration. Notably, some GRN SNPs could exert a protective effect in cognitively healthy centenarians.