Progranulinopathy: A diverse realm of disorders linked to progranulin imbalances

Abstract

Progranulin (PGRN), encoded by the GRN gene in humans, was originally isolated as a secreted growth factor that implicates in a multitude of processes ranging from regulation of tumorigenesis, inflammation to neural proliferation. Compelling evidence indicating that GRN mutation can lead to various common neuronal degenerative diseases and rare lysosomal storage diseases. These findings have unveiled a critical role for PGRN as a lysosomal protein in maintaining lysosomal function. The phenotypic spectrum of PGRN imbalance has expanded to encompass a broad spectrum of diseases, including autoimmune diseases, metabolic, musculoskeletal and cardiovascular diseases. These diseases collectively referred to as Progranulinopathy- a term encompasses the wide spectrum of disorders influenced by PGRN imbalance. Unlike its known extracellular function as a growth factor-like molecule associated with multiple membrane receptors, PGRN also serves as an intracellular co-chaperone engaged in the folding and traffic of its associated proteins, particularly the lysosomal hydrolases. This chaperone activity is required for PGRN to exert its diverse functions across a broad range of diseases, encompassing both the central nervous system and peripheral systems. In this comprehensive review, we present an update of the emerging role of PGRN in Progranulinopathy, with special focus on elucidating the intricate interplay between PGRN and a diverse array of proteins at various levels, ranging from extracellular fluids and intracellular components, as well as various pathophysiological processes involved. This review seeks to offer a comprehensive grasp of PGRN's diverse functions, aiming to unveil intricate mechanisms behind Progranulinopathy and open doors for future research endeavors.

Keywords: Autoimmune diseases; Cancer; Lysosomal Storage Diseases; Neurodegenerative Diseases; Progranulin; Progranulinopathy.

Figure 1.. Cellular pathologies induced by PGRN insufficiency.

In the brain, PGRN is most highly expressed in microglia and neurons. Lower levels of PGRN cause lysosomal dysfunction, complement activation, inflammation in microglia and nuclear pore defects, TDP-43 cytoplasmic mis-localization, and eventually death in neurons. PGRN, progranulin. TDP-43, TAR DNA-binding protein 43.

Figure 2.. PGRN and its biological effects in pathogenesis of tumor progress.

PGRN, progranulin; MMP, metalloprotease; ECM, extracellular matrix; VEGF, vascular endothelial growth factor; STAT3, Signal transducers and activators of transcription 3; SORT1, Sortilin 1; CSC, cancer stem cells; ERK, Extracellular signal-regulated kinase; PD-L1, Programmed Cell Death Ligand 1.

Figure 3.. A proposed model for explaining the role of PGRN in the cartilage and bone homeostasis.

PGRN promotes chondrocyte proliferation, differentiation, and plays a chondroprotective role through activating TNFR2 anti-inflammatory and anabolic pathway. Additionally, PGRN competitively binds to TNFR1 and blocks TNF-α mediated inflammatory and catabolic process. Via suppressing TNFR signaling, PGRN also regulates osteoclastogenesis and osteoblastogenesis, thus maintaining the bone homeostasis

Figure 4.. Schematic of the binding partners of PGRN.

PGRN interacts with its binding proteins at various locations, including extracellular matrix, cell membrane, intracellular organelles, and nuclear. The specific binding partners evoke the indicated pathways leading to multiple biological process.

Figure 5．

Progranulin deficiency in a wide spectrum of diseases -- from central nervous systems to peripheral systems, named as Progranulinopathy.