All Title Author
Keywords Abstract

PLOS ONE  2011 

Progranulin, a Glycoprotein Deficient in Frontotemporal Dementia, Is a Novel Substrate of Several Protein Disulfide Isomerase Family Proteins

DOI: 10.1371/journal.pone.0026454

Full-Text   Cite this paper   Add to My Lib


The reduced production or activity of the cysteine-rich glycoprotein progranulin is responsible for about 20% of cases of familial frontotemporal dementia. However, little is known about the molecular mechanisms that govern the level and secretion of progranulin. Here we show that progranulin is expressed in mouse cortical neurons and more prominently in mouse microglia in culture and is abundant in the endoplasmic reticulum (ER) and Golgi. Using chemical crosslinking, immunoprecipitation, and mass spectrometry, we found that progranulin is bound to a network of ER Ca2+-binding chaperones including BiP, calreticulin, GRP94, and four members of the protein disulfide isomerase (PDI) family. Loss of ERp57 inhibits progranulin secretion. Thus, progranulin is a novel substrate of several PDI family proteins and modulation of the ER chaperone network may be a therapeutic target for controlling progranulin secretion.


[1]  Vossel KA, Miller BL (2008) New approaches to the treatment of frontotemporal lobar degeneration. Curr Opin Neurol 21: 708–716.
[2]  Boxer AL, Miller BL (2005) Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord. 19: Suppl 1S36.
[3]  Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, et al. (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442: 916–919.
[4]  Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, et al. (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442: 920–924.
[5]  Gijselinck I, van der Zee J, Engelborghs S, Goossens D, Peeters K, et al. (2008) Progranulin locus deletion in frontotemporal dementia. Hum Mutat 29: 53–58.
[6]  van der Zee J, Le Ber I, Maurer-Stroh S, Engelborghs S, Gijselinck I, et al. (2007) Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia. Hum Mutat 28: 416.
[7]  Rovelet-Lecrux A, Deramecourt V, Legallic S, Maurage CA, Le Ber I, et al. (2008) Deletion of the progranulin gene in patients with frontotemporal lobar degeneration or Parkinson disease. Neurobiol Dis 31: 41–45.
[8]  Wang J, Van Damme P, Cruchaga C, Gitcho MA, Vidal JM, et al. (2010) Pathogenic cysteine mutations affect progranulin function and production of mature granulins. J Neurochem 112: 1305–1315.
[9]  Cenik B, Sephton CF, Dewey CM, Xian X, Wei S, et al. (2011) Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem 286: 16101–16108.
[10]  Jiao J, Herl LD, Farese RV, Gao F-B (2010) MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia. PLoS One 5: e10551.
[11]  Wang WX, Wilfred BR, Madathil SK, Tang G, Hu Y, et al. (2010) miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. Am J Pathol 177: 334–345.
[12]  Rademakers R, Eriksen JL, Baker M, Robinson T, Ahmed Z, et al. (2008) Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 17: 3631–3642.
[13]  Capell A, Liebscher S, Fellerer K, Brouwers N, Willem M, et al. (2011) Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase. J Neurosci 31: 1885–1894.
[14]  Hu F, Padukkavidana T, V?gter CB, Brady OA, Zheng Y, et al. (2010) Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68: 654–667.
[15]  Carrasquillo MM, Nicholson AM, Finch N, Gibbs JR, Baker M, et al. (2010) Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma. Am J Hum Genet 87: 890–897.
[16]  He Z, Bateman A (2003) Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 81: 600–612.
[17]  Petkau TL, Neal SJ, Orban PC, MacDonald JL, Hill AM, et al. (2010) Progranulin expression in the developing and adult murine brain. J Comp Neurol 518: 3931–3947.
[18]  Daniel R, Daniels E, He Z, Bateman A (2003) Progranulin (acrogranin/PC cell-derived growth factor/granulin-epithelin precursor) is expressed in the placenta, epidermis, microvasculature, and brain during murine development. Dev Dyn 227: 593–599.
[19]  Kayasuga Y, Chiba S, Suzuki M, Kikusui T, Matsuwaki T, et al. (2007) Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res 185: 110–118.
[20]  Ni M, Amy S, Lee AS (2007) ER chaperones in mammalian development and human diseases. FEBS Lett 581: 3641–3651.
[21]  Frand AR, Cuozzo JW, Kaiser CA (2000) Pathways for protein disulphide bond formation. Trends Cell Biol 10: 203–210.
[22]  Ellgaard L, Ruddock LW (2005) The human protein disulphide isomerase family: substrate interactions and functional properties. EMBO Rep 6: 28–32.
[23]  Coe H, Michalak M (2010) ERp57, a multifunctional endoplasmic reticulum resident oxidoreductase. Int J Biochem Cell Biol 42: 796–799.
[24]  Songsrirote K, Li Z, Ashford D, Bateman A, Thomas-Oates J (2010) Development and application of mass spectrometric methods for the analysis of progranulin N-glycosylation. J Proteomics 73: 1479–1490.
[25]  Oliver JD, van der Wal FJ, Bulleid NJ, High S (1997) Interaction of the thiol-dependent reductase ERp57 with nascent glycoproteins. Science 275: 86–88.
[26]  Morrice NA, Powis SJ (1998) A role for the thiol-dependent reductase ERp57 in the assembly of MHC class I molecules. Curr Biol 8: 713–716.
[27]  Rutkevich LA, Cohen-Doyle MF, Brockmeier U, Williams DB (2010) Functional relationship between protein disulfide isomerase family members during the oxidative folding of human secretory proteins. Mol Biol Cell 21: 3093–3105.
[28]  Kozlov G, Maattanen P, Schrag JD, Hura GL, Gabrielli L, et al. (2009) Structure of the noncatalytic domains and global fold of the protein disulfide isomerase ERp72. Structure 17: 651–659.
[29]  Kozlov G, Azeroual S, Rosenauer A, M??tt?nen P, Denisov AY, et al. (2010) Structure of the catalytic a(0)a fragment of the protein disulfide isomerase ERp72. J Mol Biol 401: 618–625.
[30]  Kayasuga Y, Chiba S, Suzuki M, Kikusui T, Matsuwaki T, Yamanouchi K, Kotaki H, Horai R, Iwakura Y, Nishihara M (2007) Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res 185: 110–118.


comments powered by Disqus