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Human Genetics as a Tool to Identify Progranulin Regulators

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Abstract

Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result of progranulin haploinsufficiency. These findings suggest a progranulin-dependent mechanism in this pathological FTLD subtype. Thus, identifying regulators of progranulin levels is essential for new therapies and treatments for FTLD and related disorders. In this review, we discuss the role of genetic studies in identifying progranulin regulators, beginning with the discovery of pathogenic GRN mutations and additional GRN risk variants. We also cover more recent genetic advances, including the detection of variants in the transmembrane protein 106 B gene that increase FTLD-TDP risk presumably by modulating progranulin levels and the identification of a potential progranulin receptor, sortilin. This review highlights the importance of genetic studies in the context of FTLD and further emphasizes the need for future genetic and cell biology research to continue the effort in finding a cure for progranulin-related diseases.

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References

  • Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611

    Article  PubMed  CAS  Google Scholar 

  • Baba T, Nemoto H, Watanabe K, Arai Y, Gerton GL (1993) Exon/intron organization of the gene encoding the mouse epithelin/granulin precursor (acrogranin). FEBS Lett 322:89–94

    Article  PubMed  CAS  Google Scholar 

  • Baker M, Mackenzie IR, Pickering-Brown SM et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919

    Article  PubMed  CAS  Google Scholar 

  • Bateman A, Bennett HP (2009) The granulin gene family: from cancer to dementia. Bioessays 31:1245–1254

    Article  PubMed  CAS  Google Scholar 

  • Behm-Ansmant I, Kashima I, Rehwinkel J et al (2007) mRNA quality control: an ancient machinery recognizes and degrades mRNAs with nonsense codons. FEBS Lett 581:2845–2853

    Article  PubMed  CAS  Google Scholar 

  • Bhandari V, Bateman A (1992) Structure and chromosomal location of the human granulin gene. Biochem Biophys Res Commun 188:57–63

    Article  PubMed  CAS  Google Scholar 

  • Bhandari V, Palfree RG, Bateman A (1992) Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains. Proc Natl Acad Sci USA 89:1715–1719

    Article  PubMed  CAS  Google Scholar 

  • Carrasquillo MM, Nicholson AM, Finch N 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

    Article  PubMed  CAS  Google Scholar 

  • Cruchaga C, Graff C, Chiang HH et al (2011) Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol. doi:10.1001/archneurol.2010.350

    Google Scholar 

  • Cruts M, Gijselinck I, van der Zee J et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924

    Article  PubMed  CAS  Google Scholar 

  • Daniel R, He Z, Carmichael KP, Halper J, Bateman A (2000) Cellular localization of gene expression for progranulin. J Histochem Cytochem 48:999–1009

    Article  PubMed  CAS  Google Scholar 

  • Finch N, Carrasquillo MM, Baker M et al (2011) TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 76:467–474

    Article  PubMed  CAS  Google Scholar 

  • Foster NL, Wilhelmsen K, Sima AA et al (1997) Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 41:706–715

    Article  PubMed  CAS  Google Scholar 

  • Gao X, Joselin AP, Wang L et al (2010) Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3beta. Protein Cell 1:552–562

    Article  PubMed  CAS  Google Scholar 

  • Gass J, Cannon A, Mackenzie IR et al (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001

    Article  PubMed  CAS  Google Scholar 

  • Gijselinck I, van der Zee J, Engelborghs S et al (2008) Progranulin locus deletion in frontotemporal dementia. Hum Mutat 29:53–58

    Article  PubMed  CAS  Google Scholar 

  • Graff-Radford NR, Woodruff BK (2007) Frontotemporal dementia. Semin Neurol 27:48–57

    Article  PubMed  Google Scholar 

  • Guo A, Tapia L, Bamji SX, Cynader MS, Jia W (2010) Progranulin deficiency leads to enhanced cell vulnerability and TDP-43 translocation in primary neuronal cultures. Brain Res 1366:1–8

    Article  PubMed  CAS  Google Scholar 

  • Hobert O (2008) Gene regulation by transcription factors and microRNAs. Science 319:1785–1786

    Article  PubMed  CAS  Google Scholar 

  • Hsiung GY, Fok A, Feldman HH, Rademakers R, Mackenzie IR (2011) rs5848 polymorphism and serum progranulin level. J Neurol Sci 300:28–32

    Article  PubMed  CAS  Google Scholar 

  • Hu F, Padukkavidana T, Vaegter CB et al (2010) Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68:654–667

    Article  PubMed  CAS  Google Scholar 

  • Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705

    Article  PubMed  CAS  Google Scholar 

  • Jansen P, Giehl K, Nyengaard JR et al (2007) Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nat Neurosci 10:1449–1457

    Article  PubMed  CAS  Google Scholar 

  • Kelley BJ, Haidar W, Boeve BF et al (2010) Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin. Arch Neurol 67:171–177

    Article  PubMed  Google Scholar 

  • Kleinberger G, Wils H, Ponsaerts P et al (2010) Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J Neurochem 115:735–747

    Article  PubMed  CAS  Google Scholar 

  • Le Ber I, Camuzat A, Hannequin D et al (2008) Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain 131:732–746

    Article  PubMed  Google Scholar 

  • Mackenzie IR, Baborie A, Pickering-Brown S et al (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549

    Article  PubMed  Google Scholar 

  • Mazella J, Zsurger N, Navarro V et al (1998) The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J Biol Chem 273:26273–26276

    Article  PubMed  CAS  Google Scholar 

  • Mukherjee O, Pastor P, Cairns NJ et al (2006) HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 60:314–322

    Article  PubMed  CAS  Google Scholar 

  • Mukherjee O, Wang J, Gitcho M et al (2008) Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. Hum Mutat 29:512–521

    Article  PubMed  CAS  Google Scholar 

  • Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  PubMed  CAS  Google Scholar 

  • Nilsen TW (2007) Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet 23:243–249

    Article  PubMed  CAS  Google Scholar 

  • Nykjaer A, Lee R, Teng KK et al (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427:843–848

    Article  PubMed  CAS  Google Scholar 

  • Ouellet DL, Perron MP, Gobeil LA, Plante P, Provost P (2006) MicroRNAs in gene regulation: when the smallest governs it all. J Biomed Biotechnol 2006:69616

    Article  PubMed  Google Scholar 

  • Petersen CM, Nielsen MS, Nykjaer A et al (1997) Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J Biol Chem 272:3599–3605

    Article  PubMed  CAS  Google Scholar 

  • Petkau TL, Neal SJ, Orban PC et al (2010) Progranulin expression in the developing and adult murine brain. J Comp Neurol 518:3931–3947

    Article  PubMed  Google Scholar 

  • Plowman GD, Green JM, Neubauer MG et al (1992) The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth. J Biol Chem 267:13073–13078

    PubMed  CAS  Google Scholar 

  • Poorkaj P, Bird TD, Wijsman E et al (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–825

    Article  PubMed  CAS  Google Scholar 

  • Rademakers R, Eriksen JL, Baker M 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

    Article  PubMed  CAS  Google Scholar 

  • Rizzu P, Van Swieten JC, Joosse M et al (1999) High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet 64:414–421

    Article  PubMed  CAS  Google Scholar 

  • Rollinson S, Rohrer JD, van der Zee J et al (2009) No association of PGRN 3′UTR rs5848 in frontotemporal lobar degeneration. Neurobiol Aging 32(4):754–755

    Article  PubMed  Google Scholar 

  • Shankaran SS, Capell A, Hruscha AT et al (2008) Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion. J Biol Chem 283:1744–1753

    Article  PubMed  CAS  Google Scholar 

  • Simon-Sanchez J, Seelaar H, Bochdanovits Z et al (2009) Variation at GRN 3′-UTR rs5848 is not associated with a risk of frontotemporal lobar degeneration in Dutch population. PLoS ONE 4:e7494

    Article  PubMed  Google Scholar 

  • Spillantini MG, Bird TD, Ghetti B (1998) Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 8:387–402

    Article  PubMed  CAS  Google Scholar 

  • Tang W, Lu Y, Tian QY et al (2011) The growth factor progranulin binds to tnf receptors and is therapeutic against inflammatory arthritis in mice. Science 332(6028):478–484

    Article  PubMed  CAS  Google Scholar 

  • Teng HK, Teng KK, Lee R et al (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25:5455–5463

    Article  PubMed  CAS  Google Scholar 

  • Van Damme P, Van Hoecke A, Lambrechts D et al (2008) Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 181:37–41

    Article  PubMed  Google Scholar 

  • Van Deerlin VM, Sleiman PM, Martinez-Lage M et al (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42:234–239

    Article  PubMed  Google Scholar 

  • van der Zee J, Le Ber I, Maurer-Stroh S et al (2007) Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia. Hum Mutat 28:416

    PubMed  Google Scholar 

  • van der Zee J, Van Langenhove T, Kleinberger G et al (2011) TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain 134:808–815

    Article  PubMed  Google Scholar 

  • Wang J, Van Damme P, Cruchaga C et al (2010) Pathogenic cysteine mutations affect progranulin function and production of mature granulins. J Neurochem 112:1305–1315

    Article  PubMed  CAS  Google Scholar 

  • Yin F, Banerjee R, Thomas B et al (2010) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 207:117–128

    Article  PubMed  CAS  Google Scholar 

  • Zhang YJ, Xu YF, Dickey CA et al (2007) Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. J Neurosci 27:10530–10534

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The work in the authors’ laboratory is supported by NIH grants P50AG16574, R01NS065782, R01AG26251, The ALS Association and the Consortium for Frontotemporal Dementia.

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  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Alexandra M. Nicholson, NiCole A. Finch & Rosa Rademakers

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  1. Alexandra M. Nicholson
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  2. NiCole A. Finch
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  3. Rosa Rademakers
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Correspondence to Rosa Rademakers.

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Nicholson, A.M., Finch, N.A. & Rademakers, R. Human Genetics as a Tool to Identify Progranulin Regulators. J Mol Neurosci 45, 532–537 (2011). https://doi.org/10.1007/s12031-011-9554-y

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  • DOI: https://doi.org/10.1007/s12031-011-9554-y

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