Structure, Function, and Mechanism of Progranulin; the Brain and Beyond

Overview

Journal J Mol Neurosci

Specialties Molecular Biology
Neurology

Date 2011 Jun 22

PMID 21691802

Citations 66

Authors

Huishi Toh

Babykumari P Chitramuthu

Hugh P J Bennett

Andrew Bateman

Affiliations

Soon will be listed here.

Abstract

Mutation of human GRN, the gene encoding the secreted glycoprotein progranulin, results in a form of frontotemporal lobar degeneration that is characterized by the presence of ubiquitinated inclusions containing phosphorylated and cleaved fragments of the transactivation response element DNA-binding protein-43. This has stimulated interest in understanding the role of progranulin in the central nervous system, and in particular, how this relates to neurodegeneration. Progranulin has many roles outside the brain, including regulation of cellular proliferation, survival, and migration, in cancer, including cancers of the brain, in wound repair, and inflammation. It often acts through the extracellular signal-regulated kinase and phopshatidylinositol-3-kinases pathways. The neurobiology of progranulin has followed a similar pattern with proposed roles for progranulin (PGRN) in the central nervous system as a neuroprotective agent and in neuroinflammation. Here we review the structure, biology, and mechanism of progranulin action. By understanding PGRN in a wider context, we may be better able to delineate its roles in the normal brain and in neurodegenerative disease.

Citing Articles

Microglial progranulin differently regulates hypothalamic lysosomal function in lean and obese conditions via cleavage-dependent mechanisms.

Park C, Lee C, Kang G, Min S, Kim M J Neuroinflammation. 2025; 22(1):68.

PMID: 40055725 PMC: 11887206. DOI: 10.1186/s12974-025-03370-1.

PGRN protects against serum deprivation-induced cell death by promoting the ROS scavenger system in cervical cancer.

Feng T, Xu X, Wang X, Tang W, Lu Y Cell Death Dis. 2024; 15(12):889.

PMID: 39695087 PMC: 11655951. DOI: 10.1038/s41419-024-07233-0.

Roles of organokines in intervertebral disc homeostasis and degeneration.

He Y, Liu S, Lin H, Ding F, Shao Z, Xiong L Front Endocrinol (Lausanne). 2024; 15:1340625.

PMID: 38532900 PMC: 10963452. DOI: 10.3389/fendo.2024.1340625.

Progranulin haploinsufficiency mediates cytoplasmic TDP-43 aggregation with lysosomal abnormalities in human microglia.

Sung W, Noh M, Nahm M, Kim Y, Ki C, Kim Y J Neuroinflammation. 2024; 21(1):47.

PMID: 38347588 PMC: 10863104. DOI: 10.1186/s12974-024-03039-1.

New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway.

Alnaaim S, Al-Kuraishy H, Al-Gareeb A, Ali N, Alexiou A, Papadakis M J Cell Mol Med. 2023; 27(24):3953-3965.

PMID: 37737447 PMC: 10747420. DOI: 10.1111/jcmm.17965.

References

Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H . TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006; 351(3):602-11. DOI: 10.1016/j.bbrc.2006.10.093. View

Youn B, Bang S, Kloting N, Park J, Lee N, Oh J . Serum progranulin concentrations may be associated with macrophage infiltration into omental adipose tissue. Diabetes. 2008; 58(3):627-36. PMC: 2646061. DOI: 10.2337/db08-1147. View

Canuel M, Libin Y, Morales C . The interactomics of sortilin: an ancient lysosomal receptor evolving new functions. Histol Histopathol. 2009; 24(4):481-92. DOI: 10.14670/HH-24.481. View

Liau L, Lallone R, Seitz R, Buznikov A, Gregg J, Kornblum H . Identification of a human glioma-associated growth factor gene, granulin, using differential immuno-absorption. Cancer Res. 2000; 60(5):1353-60. View

Tangkeangsirisin W, Serrero G . PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells. Carcinogenesis. 2004; 25(9):1587-92. DOI: 10.1093/carcin/bgh171. View

Moisse K, Volkening K, Leystra-Lantz C, Welch I, Hill T, Strong M . Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury. Brain Res. 2008; 1249:202-11. DOI: 10.1016/j.brainres.2008.10.021. View

He Z, Ong C, Halper J, Bateman A . Progranulin is a mediator of the wound response. Nat Med. 2003; 9(2):225-9. DOI: 10.1038/nm816. View

He Z, Bateman A . Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med (Berl). 2003; 81(10):600-12. DOI: 10.1007/s00109-003-0474-3. View

Wang W, Hayashi J, Serrero G . PC cell-derived growth factor confers resistance to dexamethasone and promotes tumorigenesis in human multiple myeloma. Clin Cancer Res. 2006; 12(1):49-56. DOI: 10.1158/1078-0432.CCR-05-0929. View

10.

Tangkeangsirisin W, Hayashi J, Serrero G . PC cell-derived growth factor mediates tamoxifen resistance and promotes tumor growth of human breast cancer cells. Cancer Res. 2004; 64(5):1737-43. DOI: 10.1158/0008-5472.can-03-2364. View

11.

Gao X, Joselin A, Wang L, Kar A, Ray P, Bateman A . Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3β. Protein Cell. 2011; 1(6):552-62. PMC: 4875315. DOI: 10.1007/s13238-010-0067-1. View

12.

He Z, Bateman A . Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo. Cancer Res. 1999; 59(13):3222-9. View

13.

Matsuwaki T, Asakura R, Suzuki M, Yamanouchi K, Nishihara M . Age-dependent changes in progranulin expression in the mouse brain. J Reprod Dev. 2010; 57(1):113-9. DOI: 10.1262/jrd.10-116s. View

14.

Caccamo A, Magri A, Oddo S . Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to Aβ oligomers accumulation. Mol Neurodegener. 2010; 5:51. PMC: 2989316. DOI: 10.1186/1750-1326-5-51. View

15.

Kayasuga Y, Chiba S, Suzuki M, Kikusui T, Matsuwaki T, Yamanouchi K . Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res. 2007; 185(2):110-8. DOI: 10.1016/j.bbr.2007.07.020. View

16.

Ahmed Z, Sheng H, Xu Y, Lin W, Innes A, Gass J . Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol. 2010; 177(1):311-24. PMC: 2893674. DOI: 10.2353/ajpath.2010.090915. View

17.

Xu D, Suenaga N, Edelmann M, Fridman R, Muschel R, Kessler B . Novel MMP-9 substrates in cancer cells revealed by a label-free quantitative proteomics approach. Mol Cell Proteomics. 2008; 7(11):2215-28. PMC: 2577209. DOI: 10.1074/mcp.M800095-MCP200. View

18.

Kessenbrock K, Frohlich L, Sixt M, Lammermann T, Pfister H, Bateman A . Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest. 2008; 118(7):2438-47. PMC: 2430496. DOI: 10.1172/JCI34694. View

19.

Carrasquillo M, Nicholson A, Finch N, Gibbs J, Baker M, Rutherford N . Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma. Am J Hum Genet. 2010; 87(6):890-7. PMC: 2997361. DOI: 10.1016/j.ajhg.2010.11.002. View

20.

Feng J, Guo F, Jiang B, Zhang Y, Frenkel S, Wang D . Granulin epithelin precursor: a bone morphogenic protein 2-inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis. FASEB J. 2010; 24(6):1879-92. PMC: 2874481. DOI: 10.1096/fj.09-144659. View