Progranulin: A conductor of receptors orchestra, a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases

Abstract

Progranulin (PGRN), a widely expressed glycoprotein with pleiotropic function, has been linked to a host of physiological processes and diverse pathological states. Currently, various therapeutic strategies targeting PGRN have been developed in a series of preclinical models of diseases and clinical trials, highlighting PGRN as a promising target in diseases treatment. Herein we summarize available knowledge of PGRN targeting in various kinds of diseases, including common neurological diseases, inflammatory autoimmune diseases, cancer, tissue repair, and rare lysosomal storage diseases, with the focus on the functional domain-oriented drug development strategies. In particular, we emphasize the potential role of PGRN as a non-conventional, extracellular matrix bound, growth factor-like conductor orchestrating multiple membrane receptors and simultaneously as an intracellular co-chaperone.

A novel mechanism of EAE resistance highlights the conflicting roles of progranulin-mediated immunosuppression and antigen processing

“…In brief, Schmitz et al present thought-provoking evidence that PGRN −/− mice are resistant to EAE. Superficial controversy between this report and previous reports documenting the prominence of PGRN as a neuroprotective and antiinflammatory molecule 1,2,[4][5][6]8,9 is assuaged by mechanistic studies embarked upon by Schmitz and colleagues. Discrepancies between baseline PGRN −/− and wild-type immunophenotypes and evaluation of endocytosis in primary monocyte cell cultures indicated a defect in antigen digestion and presentation, resulting in ineffective myelin oligodendrocyte glycoprotein processing, which could explain the association between PGRN deficiency and EAE resistance (Fig.…”

“…Progranulin (PGRN) is a secreted growth-factor-like molecule with multiple biological functions; elevated PGRN expression correlates with the activity of various autoimmune diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). [1][2][3][4] PGRN deficiency is associated with an enhanced inflammatory response and commonly results in increased susceptibility to the onset and progression of various autoimmune conditions in murine models, including inflammatory arthritis, 4 inflammatory bowel diseases, 5 and inflammatory skin diseases. 6 In contrast, PGRN expression has been shown to aggravate some autoimmune conditions, including lupus nephritis.…”

“…The impact of PGRN depletion on inflammation is, at least in part, attributable to the inhibitory effect of PGRN on inflammatory signaling of the master cytokine tumor necrosis factor (TNFα) through antagonism of TNFR1; TNF inhibitors represent the most effective biologics for management of many autoimmune inflammatory disorders, and this functional aspect of PGRN has been evaluated as an effective or promising therapeutic target in numerous inflammatory conditions. 2,[4][5][6][7] Moreover, elucidation of PGRN-mediated promotion of regulatory T-cell (Treg) activation and proliferation has highlighted the importance of PGRN as an essential factor for the stimulation and immunosuppressive potency of T cells in the inflammatory milieu. 8,9 These findings indicate the potential for the development of PGRN-targeting therapeutic strategies and a mechanistic understanding of inflammatory conditions, wherein TNFα-driven inflammation and dysregulation of the adaptive immune response direct disease onset and/or progression (Fig.…”

Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses

“…The role of progranulin in neurodegenerative diseases has recently been covered in detail in several reviews [70][71][72]. It was identified as a causal gene for autosomal recessive NCL (CLN11) in 2012, but GRN mutations were first connected to autosomal dominant frontotemporal lobar degeneration (FTLD) [73].…”

“…For a fraction of progranulin, the coordinated trafficking along with another progranulin interactor, prosaposin, may also provide a direct delivery route to the lysosome [77]. A thorough understanding of the biological functions of the full-length protein and its cleavage products has not yet been achieved, but roles in regulating inflammation, wound healing, cellular proliferation, and lysosomal function are described (as reviewed in [70][71][72]). In a recent study, it was hypothesized that progranulin might have a role in lysosomal lipid homeostasis, since a lipidome and transcriptome analysis of human brain tissue, as well as mouse brain and liver, revealed progranulin dosage-dependent changes in the metabolism of long, polyunsaturated triacylglycerides (TAGs) [78].…”