Progranulin (PGRN) (PGRN)

Progranulin (PGRN) is a pleiotropic, secreted glycoprotein encoded by the GRN gene that plays a critical role in lysosomal homeostasis, neuroprotection, and the modulation of inflammation [1, 4, 5]. In the central nervous system, PGRN is primarily expressed by neurons and microglia, where it acts as a chaperone for lysosomal enzymes like cathepsin D and glucocerebrosidase, ensuring proper protein degradation and lipid metabolism [1, 6, 9]. The Progranulin pathway involves several key receptors: Sortilin (SORT1) mediates its endocytosis and lysosomal degradation; Ephrin type-A receptor 2 (EphA2) serves as a functional signaling receptor for growth and autoregulation; and Tumor Necrosis Factor Receptors (TNFR1/2) mediate its anti-inflammatory effects [1, 12, 15]. Mutations in the GRN gene leading to haploinsufficiency are a primary cause of frontotemporal dementia (FTD-GRN), characterized by the accumulation of TDP-43 inclusions, while homozygous mutations cause the lysosomal storage disorder neuronal ceroid lipofuscinosis (NCL) [1, 3, 5]. Conversely, overexpression of PGRN is associated with tumor progression and angiogenesis in various cancers [2, 4, 12]. Therapeutic strategies currently in clinical development focus on restoring PGRN levels through gene therapy (e.g., PR006, PBFT02), protein replacement (e.g., DNL593), or by blocking its degradation via Sortilin-targeted monoclonal antibodies (e.g., Latozinemab) [13, 14, 16].

Other names

GRNAcrograninEpithelinProepithelinGranulin-epithelin precursorPC-cell-derived growth factor

Restoration of progranulin levels through gene replacement, protein delivery, or inhibition of sortilin-mediated lysosomal degradation.