Mechanisms of granulin deficiency: Lessons from cellular and animal models

Molecular Neurobiology

Volumn 47, Issue 1, 2013, Pages 337-360

  Kleinberger, Gernot ^a,b   Capell, Anja ^c   Haass, Christian ^c,d,e   Van Broeckhoven, Christine ^a,b  

^a UNIVERSITY OF ANTWERP   (Belgium)

^b UNIVERSITY OF ANTWERP   (Belgium)

^c UNIVERSITY OF MUNICH   (Germany)

^d GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^e Germany 3 Munich Cluster for Systems Neurology   (Germany)

Author keywords

Animal model; Cellular model; FTD; Granulins; Growth factor; Neurodegeneration; Progranulin; Therapy

Indexed keywords

GLYCOGEN SYNTHASE KINASE 3BETA; MITOGEN ACTIVATED PROTEIN KINASE; MITOGENIC AGENT; PHOSPHATIDYLINOSITOL 3 KINASE; PROGRANULIN;

ARTICLE; FRONTOTEMPORAL DEMENTIA; GENE EXPRESSION; GENE LOCUS; GENE MUTATION; GRANULIN DEFICIENCY; HUMAN; INFLAMMATION; LOSS OF FUNCTION MUTATION; NEUROPATHOLOGY; NONHUMAN; PROTEIN DEFICIENCY; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; SEROTONINERGIC SYSTEM; SIGNAL TRANSDUCTION; WNT SIGNALING PATHWAY;

EID: 84872497448     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-012-8380-8     Document Type: Article

References (213)

1. Cerami C, Scarpini E, Cappa SF, Galimberti D (2012) Frontotemporal lobar degeneration: current knowledge and future challenges. J Neurol 259:2278-2286
2. Van Langenhove T, van der Zee J, Van Broeckhoven C (2012) The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med (in press)
3. Neary D, Snowden J, Mann D (2005) Frontotemporal dementia. Lancet Neurol 4:771-780
4. Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DM (2009) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1-4
5. Goldman JS, Farmer JM, Wood EM, Johnson JK, Boxer A, Neuhaus J, Lomen-Hoerth C, Wilhelmsen KC, Lee VM, Grossman M, Miller BL (2005) Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 65:1817-1819
6. Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, De Jonghe P, Vandenberghe R, Santens P, De Bleecker J, Maes G, Baumer V, Dillen L, Joris G, Cuijt I, Corsmit E, Elinck E, Van Dongen J, Vermeulen S, Van den Broeck M, Vaerenberg C, Mattheijssens M, Peeters K, Robberecht W, Cras P, Martin JJ, De Deyn PP, Cruts M, Van Broeckhoven C (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11:54-65
7. Foster NL, Wilhelmsen K, Sima AA, Jones MZ, D'Amato CJ, Gilman S (1997) Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 41:706-715
8. Lynch T, Sano M, Marder KS, Bell KL, Foster NL, Defendini RF, Sima AA, Keohane C, Nygaard TG, Fahn S (1994) Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex. Neurology 44:1878-1884
9. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Heutink P (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702-705
10. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815-825
11. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 95:7737-7741
12. Cruts M, Theuns J, Van Broeckhoven C (2012) Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat. doi: 10.1002/humu.22117
13. Rademakers R, Cruts M, Van Broeckhoven C (2004) The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 24:277-295
14. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916-919
15. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920-924
16. Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC (2011) Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry 82:476-486
17. Gijselinck I, Van Broeckhoven C, Cruts M (2008) Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update. Hum Mutat 29:1373-1386
18. Sleegers K, Brouwers N, Van Broeckhoven C (2010) Role of progranulin as a biomarker for Alzheimer's disease. Biomark Med 4:37-50
19. Cruts M, Van Broeckhoven C (2008) Loss of progranulin function in frontotemporal lobar degeneration. Trends Genet 24:186-194
20. Gijselinck I, van der Zee J, Engelborghs S, Goossens D, Peeters K, Mattheijssens M, Corsmit E, Del-Favero J, De Deyn PP, Van Broeckhoven C, Cruts M (2008) Progranulin locus deletion in frontotemporal dementia. Hum Mutat 29:53-58
21. Rovelet-Lecrux A, Deramecourt V, Legallic S, Maurage CA, Le BI, Brice A, Lambert JC, Frebourg T, Hannequin D, Pasquier F, Campion D (2008) Deletion of the progranulin gene in patients with frontotemporal lobar degeneration or Parkinson disease. Neurobiol Dis 31:41-45
22. Brouwers N, Nuytemans K, van der Zee J, Gijselinck I, Engelborghs S, Theuns J, Kumar-Singh S, Pickut BA, Pals P, Dermaut B, Bogaerts V, De Pooter T, Serneels S, Van den Broeck M, Cuijt I, Mattheijssens M, Peeters K, Sciot R, Martin JJ, Cras P, Santens P, Vandenberghe R, De Deyn PP, Cruts M, Van Broeckhoven C, Sleegers K (2007) Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. Arch Neurol 64:1436-1446
23. Le Ber I, van der Zee J, Hannequin D, Gijselinck I, Campion D, Puel M, Laquerriere A, De Pooter T, Camuzat A, Van den Broeck M, Dubois B, Sellal F, Lacomblez L, Vercelletto M, Thomas-Anterion C, Michel BF, Golfier V, Didic M, Salachas F, Duyckaerts C, Cruts M, Verpillat P, Van Broeckhoven C, Brice A (2007) Progranulin null mutations in both sporadic and familial frontotemporal dementia. Hum Mutat 28:846-855
24. Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs K, Pickering-Brown SM, Graff-Radford N, Uitti R, Dickson D, Wszolek Z, Gonzalez J, Beach TG, Bigio E, Johnson N, Weintraub S, Mesulam M, White CL III, Woodruff B, Caselli R, Hsiung GY, Feldman H, Knopman D, Hutton M, Rademakers R (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988-3001
25. Le Ber I, Camuzat A, Hannequin D, Pasquier F, Guedj E, Rovelet-Lecrux A, Hahn-Barma V, van der Zee J, Clot F, Bakchine S, Puel M, Ghanim M, Lacomblez L, Mikol J, Deramecourt V, Lejeune P, de la Sayette V, Belliard S, Vercelletto M, Meyrignac C, Van Broeckhoven C, Lambert JC, Verpillat P, Campion D, Habert MO, Dubois B, Brice A (2008) Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain 131:732-746
26. Hosler BA, Siddique T, Sapp PC, Sailor W, Huang MC, Hossain A, Daube JR, Nance M, Fan C, Kaplan J, Hung WY, McKenna-Yasek D, Haines JL, Pericak-Vance MA, Horvitz HR, Brown RH Jr (2000) Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 284:1664-1669
27. Gijselinck I, Engelborghs S, Maes G, Cuijt I, Peeters K, Mattheijssens M, Joris G, Cras P, Martin JJ, De Deyn PP, Kumar-Singh S, Van Broeckhoven C, Cruts M (2010) Identification of 2 loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol 67:606-616
28. Morita M, Al Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, Mitchell JE, Habgood JJ, de Belleroche J, Xi J, Jongjaroenprasert W, Horvitz HR, Gunnarsson LG, Brown RH Jr (2006) A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66:839-844
29. Rollinson S, Mead S, Snowden J, Richardson A, Rohrer J, Halliwell N, Usher S, Neary D, Mann D, Hardy J, Pickering-Brown S (2011) Frontotemporal lobar degeneration genome wide association study replication confirms a risk locus shared with amyotrophic lateral sclerosis. Neurobiol Aging 32:758-7
30. Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, Siddique T, Schelhaas HJ, Kusters B, Troost D, Baas F, de J, V, Shaw CE (2006) Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain 129:868-876
31. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245-256
32. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257-268
33. Galimberti D, Scarpini E (2012) Genetics of frontotemporal lobar degeneration. Front Neurol 3:52
34. Hardy J, Singleton A (2009) Genomewide association studies and human disease. N Engl J Med 360:1759-1768
35. Lang CM, Fellerer K, Schwenk BM, Kuhn PH, Kremmer E, Edbauer D, Capell A (2012) Haass C (2012) Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. J Biol Chem 287(23):19355-19365
36. Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, Arnold SE, Mann DM, Pickering-Brown SM, Seelaar H, Heutink P, van Swieten JC, Murrell JR, Ghetti B, Spina S, Grafman J, Hodges J, Spillantini MG, Gilman S, Lieberman AP, Kaye JA, Woltjer RL, Bigio EH, Mesulam M, Al-Sarraj S, Troakes C, Rosenberg RN, White CL III, Ferrer I, Llado A, Neumann M, Kretzschmar HA, Hulette CM, Welsh-Bohmer KA, Miller BL, Alzualde A, de Lopez MA, McKee AC, Gearing M, Levey AI, Lah JJ, Hardy J, Rohrer JD, Lashley T, Mackenzie IR, Feldman HH, Hamilton RL, DeKosky ST, van der Zee J, Kumar-Singh S, Van Broeckhoven C, Mayeux R, Vonsattel JP, Troncoso JC, Kril JJ, Kwok JB, Halliday GM, Bird TD, Ince PG, Shaw PJ, Cairns NJ, Morris JC, McLean CA, DeCarli C, Ellis WG, Freeman SH, Frosch MP, Growdon JH, Perl DP, Sano M, Bennett DA, Schneider JA, Beach TG, Reiman EM, Woodruff BK, Cummings J, Vinters HV, Miller CA, Chui HC, Alafuzoff I, Hartikainen P, Seilhean D, Galasko D, Masliah E, Cotman CW, Tunon MT, Martinez MC, Munoz DG, Carroll SL, Marson D, Riederer PF, Bogdanovic N, Schellenberg GD, Hakonarson H, Trojanowski JQ, Lee VM (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42:234-239
37. van der Zee J, Van Broeckhoven C (2011) TMEM106B a novel risk factor for frontotemporal lobar degeneration. J Mol Neurosci 45:516-521
38. van der Zee J, Van Langenhove T, Kleinberger G, Sleegers K, Engelborghs S, Vandenberghe R, Santens P, Van den Broeck M, Joris G, Brys J, Mattheijssens M, Peeters K, Cras P, De Deyn PP, Cruts M, Van Broeckhoven C (2011) TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain 134:808-815
39. Cruchaga C, Graff C, Chiang HH, Wang J, Hinrichs AL, Spiegel N, Bertelsen S, Mayo K, Norton JB, Morris JC, Goate A (2011) Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol 68:581-586
40. Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L, Busch JI, Akle S, Grossman M, Van DV, Trojanowski JQ, Lee VM (2012) TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci 32:11213-11227
41. Brady OA, Zheng Y, Murphy K, Huang M, Hu F (2012) The Frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet (in press)
42. Carrasquillo MM, Nicholson AM, Finch N, Gibbs JR, Baker M, Rutherford NJ, Hunter TA, DeJesus-Hernandez M, Bisceglio GD, Mackenzie IR, Singleton A, Cookson MR, Crook JE, Dillman A, Hernandez D, Petersen RC, Graff-Radford NR, Younkin SG, Rademakers R (2010) Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma. Am J Hum Genet 87:890-897
43. Kelley BJ, Haidar W, Boeve BF, Baker M, Graff-Radford NR, Krefft T, Frank AR, Jack CR Jr, Shiung M, Knopman DS, Josephs KA, Parashos SA, Rademakers R, Hutton M, Pickering-Brown S, Adamson J, Kuntz KM, Dickson DW, Parisi JE, Smith GE, Ivnik RJ, Petersen RC (2009) Prominent phenotypic variability associated with mutations in progranulin. Neurobiol Aging 30:739-751
44. Larner AJ (2012) Intrafamilial clinical phenotypic heterogeneity with progranulin gene p.Glu498fs mutation. J Neurol Sci 316:189-190
45. Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M (2007) Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C->T (Arg493X) mutation: an international initiative. Lancet Neurol 6:857-868
46. van Swieten JC, Heutink P (2008) Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia. Lancet Neurol 7:965-974
47. Cruchaga C, Fernandez-Seara MA, Seijo-Martinez M, Samaranch L, Lorenzo E, Hinrichs A, Irigoyen J, Maestro C, Prieto E, Marti-Climent JM, Arbizu J, Pastor MA, Pastor P (2009) Cortical atrophy and language network reorganization associated with a novel progranulin mutation. Cereb Cortex 19:1751-1760
48. Guerreiro RJ, Santana I, Bras JM, Revesz T, Rebelo O, Ribeiro MH, Santiago B, Oliveira CR, Singleton A, Hardy J (2008) Novel progranulin mutation: screening for PGRN mutations in a Portuguese series of FTD/CBS cases. Mov Disord 23:1269-1273
49. Rainero I, Rubino E, Negro E, Gallone S, Galimberti D, Gentile S, Scarpini E, Pinessi L (2011) Heterosexual pedophilia in a frontotemporal dementia patient with a mutation in the progranulin gene. Biol Psychiatry 70:e43-e44
50. Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, Rutherford NJ, Baker M, Knopman DS, Wszolek ZK, Parisi JE, Dickson DW, Petersen RC, Rademakers R, Jack CR Jr, Josephs KA (2012) Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 135:794-806
51. Rohrer JD, Ridgway GR, Modat M, Ourselin S, Mead S, Fox NC, Rossor MN, Warren JD (2010) Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations. NeuroImage 53:1070-1076
52. Whitwell JL, Weigand SD, Gunter JL, Boeve BF, Rademakers R, Baker M, Knopman DS, Wszolek ZK, Petersen RC, Jack CR Jr, Josephs KA (2011) Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN. Neurology 77:393-398
53. Borroni B, Alberici A, Cercignani M, Premi E, Serra L, Cerini C, Cosseddu M, Pettenati C, Turla M, Archetti S, Gasparotti R, Caltagirone C, Padovani A, Bozzali M (2012) Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD. Neurobiol Aging 33(10):2506-2520
54. Mackenzie IR (2007) The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropathol 114:49-54
55. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (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
56. Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle F, Morita M, Nakano I, Oda T, Tsuchiya K, Akiyama H (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64:60-70
57. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130-133
58. Kumar-Singh S (2011) Progranulin and TDP-43: mechanistic links and future directions. J Mol Neurosci 45:561-573
59. Bhandari V, Bateman A (1992) Structure and chromosomal location of the human granulin gene. Biochem Biophys Res Commun 188:57-63
60. Bateman A, Bennett HP (1998) Granulins: the structure and function of an emerging family of growth factors. J Endocrinol 158:145-151
61. Bucan M, Gatalica B, Baba T, Gerton GL (1996) Mapping of Grn, the gene encoding the granulin/epithelin precursor (acrogranin), to mouse chromosome 11. Mamm Genome 7:704-705
62. Bhandari V, Giaid A, Bateman A (1993) The complementary deoxyribonucleic acid sequence, tissue distribution, and cellular localization of the rat granulin precursor. Endocrinology 133:2682-2689
63. 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 U S A 89:1715-1719
64. Bateman A, Belcourt D, Bennett H, Lazure C, Solomon S (1990) Granulins, a novel class of peptide from leukocytes. Biochem Biophys Res Commun 173:1161-1168
65. Shoyab M, McDonald VL, Byles C, Todaro GJ, Plowman GD (1990) Epithelins 1 and 2: isolation and characterization of two cysteine-rich growth-modulating proteins. Proc Natl Acad Sci U S A 87:7912-7916
66. Baba T, Hoff HB III, Nemoto H, Lee H, Orth J, Arai Y, Gerton GL (1993) Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins, and epithelins, and is expressed in somatic as well as male germ cells. Mol Reprod Dev 34:233-243
67. Parnell PG, Wunderlich J, Carter B, Halper J (1992) Transforming growth factor e: amino acid analysis and partial amino acid sequence. Growth Factors 7:65-72
68. Plowman GD, Green JM, Neubauer MG, Buckley SD, McDonald VL, Todaro GJ, Shoyab M (1992) The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth. J Biol Chem 267:13073-13078
69. Zhou J, Gao G, Crabb JW, Serrero G (1993) Purification of an autocrine growth factor homologous with mouse epithelin precursor from a highly tumorigenic cell line. J Biol Chem 268:10863-10869
70. 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 U S A 89:1715-1719
71. Petkau TL, Neal SJ, Orban PC, MacDonald JL, Hill AM, Lu G, Feldman HH, Mackenzie IR, Leavitt BR (2010) Progranulin expression in the developing and adult murine brain. J Comp Neurol 518:3931-3947
72. Daniel R, He Z, Carmichael KP, Halper J, Bateman A (2000) Cellular localization of gene expression for progranulin. J Histochem Cytochem 48:999-1009
73. Matsuwaki T, Asakura R, Suzuki M, Yamanouchi K, Nishihara M (2011) Age-dependent changes in progranulin expression in the mouse brain. J Reprod Dev 57:113-119
74. 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
75. 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
76. Suzuki M, Yoshida S, Nishihara M, Takahashi M (1998) Identification of a sex steroid-inducible gene in the neonatal rat hypothalamus. Neurosci Lett 242:127-130
77. Jiao J, Herl LD, Farese RV, Gao FB (2010) MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia. PLoS One 5:e10551
78. Rademakers R, Eriksen JL, Baker M, Robinson T, Ahmed Z, Lincoln SJ, Finch N, Rutherford NJ, Crook RJ, Josephs KA, Boeve BF, Knopman DS, Petersen RC, Parisi JE, Caselli RJ, Wszolek ZK, Uitti RJ, Feldman H, Hutton ML, Mackenzie IR, Graff-Radford NR, Dickson DW (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
79. Wang WX, Kyprianou N, Wang X, Nelson PT (2010) Dysregulation of the mitogen granulin in human cancer through the miR-15/107 microRNA gene group. Cancer Res 70:9137-9142
80. Wang WX, Wilfred BR, Madathil SK, Tang G, Hu Y, Dimayuga J, Stromberg AJ, Huang Q, Saatman KE, Nelson PT (2010) miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. Am J Pathol 177:334-345
81. Kocerha J, Kouri N, Baker M, Finch N, DeJesus-Hernandez M, Gonzalez J, Chidamparam K, Josephs KA, Boeve BF, Graff-Radford NR, Crook J, Dickson DW, Rademakers R (2011) Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations. BMC Genomics 12:527
82. Galimberti D, D'Addario C, Dell'osso B, Fenoglio C, Marcone A, Cerami C, Cappa SF, Palazzo MC, Arosio B, Mari D, Maccarrone M, Bresolin N, Altamura AC, Scarpini E (2012) Progranulin gene (GRN) promoter methylation is increased in patients with sporadic frontotemporal lobar degeneration. Neurol Sci (in press)
83. Suh HS, Choi N, Tarassishin L, Lee SC (2012) Regulation of progranulin expression in human microglia and proteolysis of progranulin by matrix metalloproteinase-12 (MMP-12). PLoS One 7:e35115
84. Swindell WR (2009) Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse. BMC Genomics 10:585
85. Jurgens HA, Johnson RW (2012) Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation. Exp Neurol 233:40-48
86. Tolkatchev D, Malik S, Vinogradova A, Wang P, Chen Z, Xu P, Bennett HP, Bateman A, Ni F (2008) Structure dissection of human progranulin identifies well-folded granulin/epithelin modules with unique functional activities. Protein Sci 17:711-724
87. Hrabal R, Chen Z, James S, Bennett HP, Ni F (1996) The hairpin stack fold, a novel protein architecture for a new family of protein growth factors. Nat Struct Biol 3:747-752
88. De Muynck L, Van Damme P (2011) Cellular effects of progranulin in health and disease. J Mol Neurosci 45:549-560
89. Toh H, Chitramuthu BP, Bennett HP, Bateman A (2011) Structure, function, and mechanism of progranulin; the brain and beyond. J Mol Neurosci 45:538-548
90. Van Damme P, Van Hoecke A, Lambrechts D, Vanacker P, Bogaert E, van Swieten J, Carmeliet P, Van Den Bosch L, Robberecht W (2008) Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 181:37-41
91. Gao X, Joselin AP, Wang L, Kar A, Ray P, Bateman A, Goate AM, Wu JY (2010) Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3beta. Protein Cell 1:552-562
92. Gass J, Lee WC, Cook C, Finch N, Stetler C, Jansen-West K, Lewis J, Link CD, Rademakers R, Nykjaer A, Petrucelli L (2012) Progranulin regulates neuronal outgrowth independent of sortilin. Mol Neurodegener 7:33
93. Wang J, Van Damme P, Cruchaga C, Gitcho MA, Vidal JM, Seijo-Martinez M, Wang L, Wu JY, Robberecht W, Goate A (2010) Pathogenic cysteine mutations affect progranulin function and production of mature granulins. J Neurochem 112:1305-1315
94. Kleinberger G, Wils H, Joris G, Ponsaerts P, Timmermans J-P, Van Broeckhoven C, Kumar-Singh S (2010) Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J Neurochem 115:735-747
95. Xu J, Xilouri M, Bruban J, Shioi J, Shao Z, Papazoglou I, Vekrellis K, Robakis NK (2011) Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 32:2326.e5-2326.e16
96. Feng JQ, Guo FJ, Jiang BC, Zhang Y, Frenkel S, Wang DW, Tang W, Xie Y, Liu CJ (2010) Granulin epithelin precursor: a bone morphogenic protein 2-inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis. FASEB J 24:1879-1892
97. Monami G, Gonzalez EM, Hellman M, Gomella LG, Baffa R, Iozzo RV, Morrione A (2006) Proepithelin promotes migration and invasion of 5637 bladder cancer cells through the activation of ERK1/2 and the formation of a paxillin/FAK/ERK complex. Cancer Res 66:7103-7110
98. Ong CH, Bateman A (2003) Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. Histol Histopathol 18:1275-1288
99. Zanocco-Marani T, Bateman A, Romano G, Valentinis B, He ZH, Baserga R (1999) Biological activities and signaling pathways of the granulin/epithelin precursor. Cancer Res 59:5331-5340
100. Matsubara T, Mita A, Minami K, Hosooka T, Kitazawa S, Takahashi K, Tamori Y, Yokoi N, Watanabe M, Matsuo E, Nishimura O, Seino S (2012) PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue. Cell Metab 15:38-50
101. Xu SQ, Tang D, Chamberlain S, Pronk G, Masiarz FR, Kaur S, Prisco M, Zanocco-Marani T, Baserga R (1998) The granulin/epithelin precursor abrogates the requirement for the insulin-like growth factor 1 receptor for growth in vitro. J Biol Chem 273:20078-20083
102. Hu SY, Tai CC, Li YH, Wu JL (2012) Progranulin compensates for blocked IGF-1 signaling to promote myotube hypertrophy in C2C12 myoblasts via the PI3K/Akt/mTOR pathway. FEBS Lett 586:3485-3492
103. Culouscou JM, Carlton GW, Shoyab M (1993) Biochemical analysis of the epithelin receptor. J Biol Chem 268:10458-10462
104. Xia X, Serrero G (1998) Identification of cell surface binding sites for PC-cell-derived growth factor, PCDGF, (epithelin/granulin precursor) on epithelial cells and fibroblasts. Biochem Biophys Res Commun 245:539-543
105. Parnell PG, Carter BJ, Halper J (1995) Identification of a membrane-associated receptor for transforming growth factor type E. J Recept Signal Transduct Res 15:747-756
106. Braulke T, Bonifacino JS (2009) Sorting of lysosomal proteins. Biochim Biophys Acta 1793:605-614
107. Hu F, Padukkavidana T, Vaegter CB, Brady OA, Zheng Y, Mackenzie IR, Feldman HH, Nykjaer A, Strittmatter SM (2010) Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68:654-667
108. Zheng Y, Brady OA, Meng PS, Mao Y, Hu F (2011) C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking. PLoS One 6:e21023
109. Nykjaer A, Willnow TE (2012) Sortilin: a receptor to regulate neuronal viability and function. Trends Neurosci 35:261-270
110. Bhandari V, Daniel R, Lim PS, Bateman A (1996) Structural and functional analysis of a promoter of the human granulin/epithelin gene. Biochem J 319(Pt 2):441-447
111. He Z, Ong CH, Halper J, Bateman A (2003) Progranulin is a mediator of the wound response. Nat Med 9:225-229
112. Kessenbrock K, Frohlich L, Sixt M, Lammermann T, Pfister H, Bateman A, Belaaouaj A, Ring J, Ollert M, Fassler R, Jenne DE (2008) Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest 118:2438-2447
113. Tang W, Lu Y, Tian QY, Zhang Y, Guo FJ, Liu GY, Syed NM, Lai Y, Lin EA, Kong L, Su J, Yin F, Ding AH, Zanin-Zhorov A, Dustin ML, Tao J, Craft J, Yin Z, Feng JQ, Abramson SB, Yu XP, Liu CJ (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332:478-484
114. Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF, Nathan C, Ding A (2009) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 207:117-128
115. Zhu J, Nathan C, Jin W, Sim D, Ashcroft GS, Wahl SM, Lacomis L, Erdjument-Bromage H, Tempst P, Wright CD, Ding A (2002) Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 111:867-878
116. Bai XH, Wang DW, Kong L, Zhang Y, Luan Y, Kobayashi T, Kronenberg HM, Yu XP, Liu CJ (2009) ADAMTS-7, a direct target of PTHrP, adversely regulates endochondral bone growth by associating with and inactivating GEP growth factor. Mol Cell Biol 29:4201-4219
117. Butler GS, Dean RA, Tam EM, Overall CM (2008) Pharmacoproteomics of a metalloproteinase hydroxamate inhibitor in breast cancer cells: dynamics of membrane type 1 matrix metalloproteinase-mediated membrane protein shedding. Mol Cell Biol 28:4896-4914
118. Xu D, Suenaga N, Edelmann MJ, Fridman R, Muschel RJ, Kessler BM (2008) Novel MMP-9 substrates in cancer cells revealed by a label-free quantitative proteomics approach. Mol Cell Proteomics 7:2215-2228
119. Ashcroft GS, Lei K, Jin W, Longenecker G, Kulkarni AB, Greenwell-Wild T, Hale-Donze H, McGrady G, Song XY, Wahl SM (2000) Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nat Med 6:1147-1153
120. Tang W, Lu Y, Tian QY, Zhang Y, Guo FJ, Liu GY, Syed NM, Lai Y, Lin EA, Kong L, Su J, Yin F, Ding AH, Zanin-Zhorov A, Dustin ML, Tao J, Craft J, Yin Z, Feng JQ, Abramson SB, Yu XP, Liu CJ (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 32:478-484
121. Okura H, Yamashita S, Ohama T, Saga A, Yamamoto-Kakuta A, Hamada Y, Sougawa N, Ohyama R, Sawa Y, Matsuyama A (2010) HDL/apolipoprotein A-I binds to macrophage-derived progranulin and suppresses its conversion into proinflammatory granulins. J Atheroscler Thromb 17:568-577
122. Park B, Buti L, Lee S, Matsuwaki T, Spooner E, Brinkmann MM, Nishihara M, Ploegh HL (2011) Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity 34:505-513
123. Moresco EM, Beutler B (2011) Special delivery: granulin brings CpG DNA to Toll-like receptor 9. Immunity 34:453-455
124. Pickford F, Marcus J, Camargo LM, Xiao Q, Graham D, Mo JR, Burkhardt M, Kulkarni V, Crispino J, Hering H, Hutton M (2011) Progranulin is a chemoattractant for microglia and stimulates their endocytic activity. Am J Pathol 178:284-295
125. Baker CA, Manuelidis L (2003) Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease. Proc Natl Acad Sci U S A 100:675-679
126. Gliebus G, Rosso A, Lippa CF (2009) Progranulin and beta-amyloid distribution: a case report of the brain from preclinical PS-1 mutation carrier. Am J Alzheimers Dis Other Demen 24:456-460
127. Malaspina A, Kaushik N, de BJ (2001) Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays. J Neurochem 77:132-145
128. Chen-Plotkin AS, Xiao J, Geser F, Martinez-Lage M, Grossman M, Unger T, Wood EM, Van Deerlin VM, Trojanowski JQ, Lee VM (2010) Brain progranulin expression in GRN-associated frontotemporal lobar degeneration. Acta Neuropathol 119:111-122
129. Pereson S, Wils H, Kleinberger G, McGowan E, Vandewoestyne M, Van Broeck B, Joris G, Cuijt I, Deforce D, Hutton M, Van Broeckhoven C, Kumar-Singh S (2009) Progranulin expression correlates with dense-core amyloid plaque burden in Alzheimer disease mouse models. J Pathol 219:173-181
130. Ferraiuolo L, Heath PR, Holden H, Kasher P, Kirby J, Shaw PJ (2007) Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS. J Neurosci 27:9201-9219
131. Lobsiger CS, Boillee S, Cleveland DW (2007) Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc Natl Acad Sci U S A 104:7319-7326
132. Philips T, De Muynck L, Thu HN, Weynants B, Vanacker P, Dhondt J, Sleegers K, Schelhaas HJ, Verbeek M, Vandenberghe R, Sciot R, Van Broeckhoven C, Lambrechts D, Van Leuven F, Van Den Bosch L, Robberecht W, Van Damme P (2010) Microglial upregulation of progranulin as a marker of motor neuron degeneration. J Neuropathol Exp Neurol 69:1191-1200
133. Sjogren M, Folkesson S, Blennow K, Tarkowski E (2004) Increased intrathecal inflammatory activity in frontotemporal dementia: pathophysiological implications. J Neurol Neurosurg Psychiatry 75:1107-1111
134. Bossu P, Salani F, Alberici A, Archetti S, Bellelli G, Galimberti D, Scarpini E, Spalletta G, Caltagirone C, Padovani A, Borroni B (2011) Loss of function mutations in the progranulin gene are related to pro-inflammatory cytokine dysregulation in frontotemporal lobar degeneration patients. J Neuroinflammation 8:65
135. McGeer EG, McGeer PL (2003) Inflammatory processes in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 27:741-749
136. Hirsch EC, Vyas S, Hunot S (2012) Neuroinflammation in Parkinson's disease. Parkinsonism Relat Disord 18(Suppl 1):S210-S212
137. Bruce-Keller AJ, Keller JN, Morrison CD (2009) Obesity and vulnerability of the CNS. Biochim Biophys Acta 1792:395-400
138. Luchsinger JA, Gustafson DR (2009) Adiposity, type 2 diabetes, and Alzheimer's disease. J Alzheimers Dis 16:693-704
139. Kim B, Feldman EL (2012) Insulin resistance in the nervous system. Trends Endocrinol Metab 23:133-141
140. Youn BS, Bang SI, Kloting N, Park JW, Lee N, Oh JE, Pi KB, Lee TH, Ruschke K, Fasshauer M, Stumvoll M, Bluher M (2009) Serum progranulin concentrations may be associated with macrophage infiltration into omental adipose tissue. Diabetes 58:627-636
141. Richter J, Focke D, Ebert T, Kovacs P, Bachmann A, Lossner U, Kralisch S, Kratzsch J, Beige J, Anders M, Bast I, Bluher M, Stumvoll M, Fasshauer M (2012) Serum levels of the adipokine progranulin depend on renal function. Diabetes Care (in press)
142. Kloting N, Fasshauer M, Dietrich A, Kovacs P, Schon MR, Kern M, Stumvoll M, Bluher M (2010) Insulin-sensitive obesity. Am J Physiol Endocrinol Metab 299:E506-E515
143. Kim HK, Shin MS, Youn BS, Namkoong C, Gil SY, Kang GM, Yu JH, Kim MS (2011) Involvement of progranulin in hypothalamic glucose sensing and feeding regulation. Endocrinology 152:4672-4682
144. Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JS, Shears S, Behrens MI, Budde J, Hinrichs AL, Norton J, Levitch D, Taylor-Reinwald L, Gitcho M, Tu PH, Tenenholz GL, Liscic RM, Armendariz J, Morris JC, Goate AM (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
145. Mukherjee O, Wang J, Gitcho M, Chakraverty S, Taylor-Reinwald L, Shears S, Kauwe JS, Norton J, Levitch D, Bigio EH, Hatanpaa KJ, White CL, Morris JC, Cairns NJ, Goate A (2008) Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. Hum Mutat 29:512-521
146. Shankaran SS, Capell A, Hruscha AT, Fellerer K, Neumann M, Schmid B, Haass C (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
147. Hoque M, Mathews MB, Pe'ery T (2010) Progranulin (granulin/epithelin precursor) and its constituent granulin repeats repress transcription from cellular promoters. J Cell Physiol 223:224-233
148. Hoque M, Young TM, Lee CG, Serrero G, Mathews MB, Pe'ery T (2003) The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription. Mol Cell Biol 23:1688-1702
149. Chen-Plotkin AS, Geser F, Plotkin JB, Clark CM, Kwong LK, Yuan W, Grossman M, Van Deerlin VM, Trojanowski JQ, Lee VM (2008) Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration. Hum Mol Genet 17:1349-1362
150. Guo Z, Li Q, Han Y, Liang Y, Xu Z, Ren T (2012) Prevention of LPS-induced acute lung injury in mice by progranulin. Mediators Inflamm 2012:540794
151. Bateman A, Bennett HP (2009) The granulin gene family: from cancer to dementia. Bioessays 31:1245-1254
152. Liu Y, Xi L, Liao G, Wang W, Tian X, Wang B, Chen G, Han Z, Wu M, Wang S, Zhou J, Xu G, Lu Y, Ma D (2007) Inhibition of PC cell-derived growth factor (PCDGF)/granulin-epithelin precursor (GEP) decreased cell proliferation and invasion through downregulation of cyclin D and CDK4 and inactivation of MMP-2. BMC Cancer 7:22
153. Lu R, Serrero G (2001) Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor). Proc Natl Acad Sci U S A 98:142-147
154. Park MY, Park YS, Nam JH (2011) RNA interference against granulin-epithelin precursor prevents hepatocellular carcinoma growth: its application as a therapeutic agent. Int J Oncol 39:853-861
155. 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.
156. Kamrava M, Simpkins F, Alejandro E, Michener C, Meltzer E, Kohn EC (2005) Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin-epithelin precursor (GEP), a prosurvival factor for ovarian cancer. Oncogene 24:7084-7093
157. Kong WJ, Zhang SL, Chen X, Zhang S, Wang YJ, Zhang D, Sun Y (2007) PC cell-derived growth factor overexpression promotes proliferation and survival of laryngeal carcinoma. Anticancer Drugs 18:29-40
158. Zhang YJ, Xu YF, Dickey CA, Buratti E, Baralle F, Bailey R, Pickering-Brown S, Dickson D, Petrucelli L (2007) Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. J Neurosci 27:10530-10534
159. Brouwers N, Sleegers K, Engelborghs S, Maurer-Stroh S, Gijselinck I, van der Zee J, Pickut BA, Van den Broeck M, Mattheijssens M, Peeters K, Schymkowitz J, Rousseau F, Martin JJ, Cruts M, De Deyn PP, Van Broeckhoven C (2008) Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology 71:656-664
160. Sleegers K, Brouwers N, Maurer-Stroh S, van Es MA, Van Damme P, van Vught PW, van der Zee J, Serneels S, De Pooter T, Van den Broeck M, Cruts M, Schymkowitz J, De Jonghe P, Rousseau F, van den Berg LH, Robberecht W, Van Broeckhoven C (2008) Progranulin genetic variability contributes to amyotrophic lateral sclerosis. Neurology 71:253-259
161. Almeida S, Zhang Z, Coppola G, Mao W, Futai K, Karydas A, Geschwind MD, Tartaglia MC, Gao F, Gianni D, Sena-Esteves M, Geschwind DH, Miller BL, Farese RV Jr, Gao FB (2012) Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects. Cell Rep 2:789-798
162. Nedachi T, Kawai T, Matsuwaki T, Yamanouchi K, Nishihara M (2011) Progranulin enhances neural progenitor cell proliferation through glycogen synthase kinase 3beta phosphorylation. Neuroscience 185:106-115
163. Rosen EY, Wexler EM, Versano R, Coppola G, Gao F, Winden KD, Oldham MC, Martens LH, Zhou P, Farese RV Jr, Geschwind DH (2011) Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating wnt signaling. Neuron 71:1030-1042
164. Ryan CL, Baranowski DC, Chitramuthu BP, Malik S, Li Z, Cao M, Minotti S, Durham HD, Kay DG, Shaw CA, Bennett HP, Bateman A (2009) Progranulin is expressed within motor neurons and promotes neuronal cell survival. BMC Neurosci 10:130
165. Tapia L, Milnerwood A, Guo A, Mills F, Yoshida E, Vasuta C, Mackenzie IR, Raymond L, Cynader M, Jia W, Bamji SX (2011) Progranulin deficiency decreases gross neural connectivity but enhances transmission at individual synapses. J Neurosci 31:11126-11132
166. Jope RS, Johnson GV (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29:95-102
167. Petkau TL, Neal SJ, Milnerwood A, Mew A, Hill AM, Orban P, Gregg J, Lu G, Feldman HH, Mackenzie IR, Raymond LA, Leavitt BR (2012) Synaptic dysfunction in progranulin-deficient mice. Neurobiol Dis 45:711-722
168. Sleegers K, Cruts M, Van BC (2010) Molecular pathways of frontotemporal lobar degeneration. Annu Rev Neurosci 33:71-88
169. Lim HY, Albuquerque B, Haussler A, Myrczek T, Ding A, Tegeder I (2012) Progranulin contributes to endogenous mechanisms of pain defense after nerve injury in mice. J Cell Mol Med 16:708-721
170. Dormann D, Capell A, Carlson AM, Shankaran SS, Rodde R, Neumann M, Kremmer E, Matsuwaki T, Yamanouchi K, Nishihara M, Haass C (2009) Proteolytic processing of TAR DNA binding protein-43 by caspases produces C-terminal fragments with disease defining properties independent of progranulin. J Neurochem 110:1082-1094
171. Igaz LM, Kwong LK, Chen-Plotkin A, Winton MJ, Unger TL, Xu Y, Neumann M, Trojanowski JQ, Lee VM (2009) Expression of TDP-43 C-terminal fragments in vitro recapitulates pathological features of TDP-43 proteinopathies. J Biol Chem 284:8516-8524
172. Cadieux B, Chitramuthu BP, Baranowski D, Bennett HP (2005) The zebrafish progranulin gene family and antisense transcripts. BMC Genomics 6:156
173. Kao AW, Eisenhut RJ, Martens LH, Nakamura A, Huang A, Bagley JA, Zhou P, De LA, Neukomm LJ, Cabello J, Farese RV Jr, Kenyon C (2011) A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc Natl Acad Sci U S A 108:4441-4446
174. Pera EM, Hou S, Strate I, Wessely O, De Robertis EM (2005) Exploration of the extracellular space by a large-scale secretion screen in the early Xenopus embryo. Int J Dev Biol 49:781-796
175. Li YH, Chen MH, Gong HY, Hu SY, Li YW, Lin GH, Lin CC, Liu W, Wu JL (2010) Progranulin A-mediated MET signaling is essential for liver morphogenesis in zebrafish. J Biol Chem 285:41001-41009
176. Chitramuthu BP, Baranowski DC, Kay DG, Bateman A, Bennett HP (2010) Progranulin modulates zebrafish motoneuron development in vivo and rescues truncation defects associated with knockdown of survival motor neuron 1. Mol Neurodegener 5:41
177. Laird AS, Van Hoecke A, De Muynck L, Timmers M, Van Den Bosch L, Van Damme P, Robberecht W (2010) Progranulin is neurotrophic in vivo and protects against a mutant TDP-43 induced axonopathy. PLoS One 5:e13368
178. Wils H, Kleinberger G, Pereson S, Janssens J, Capell A, Van Dam D, Cuijt I, Joris G, De Deyn PP, Haass C, Van Broeckhoven C, Kumar-Singh S (2012) Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice. J Pathol 228(1):67-76
179. Martens LH, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, Min SW, Gan L, Finkbeiner S, Huang EJ, Farese RV Jr (2012) Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest 122:3955-3959
180. Ahmed Z, Sheng H, Xu YF, Lin WL, Innes AE, Gass J, Yu X, Hou H, Chiba S, Yamanouchi K, Leissring M, Petrucelli L, Nishihara M, Hutton ML, McGowan E, Dickson DW, Lewis J (2010) Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggests a role for progranulin in successful aging. Am J Pathol 177:311-324
181. Ghoshal N, Dearborn JT, Wozniak DF, Cairns NJ (2012) Core features of frontotemporal dementia recapitulated in progranulin knockout mice. Neurobiol Dis 45:395-408
182. Suzuki M, Bannai M, Matsumuro M, Furuhata Y, Ikemura R, Kuranaga E, Kaneda Y, Nishihara M, Takahashi M (2000) Suppression of copulatory behavior by intracerebroventricular infusion of antisense oligodeoxynucleotide of granulin in neonatal male rats. Physiol Behav 68:707-713
183. Suzuki M, Lee HC, Kayasuga Y, Chiba S, Nedachi T, Matsuwaki T, Yamanouchi K, Nishihara M (2009) Roles of progranulin in sexual differentiation of the developing brain and adult neurogenesis. J Reprod Dev 55:351-355
184. Suzuki M, Nishiahara M (2002) Granulin precursor gene: a sex steroid-inducible gene involved in sexual differentiation of the rat brain. Mol Genet Metab 75:31-37
185. Chiba S, Matsuwaki T, Yamanouchi K, Nishihara M (2009) Alteration in anxiety with relation to the volume of the locus ceruleus in progranulin-deficient mice. J Reprod Dev 55:518-522
186. Yin F, Dumont M, Banerjee R, Ma Y, Li H, Lin MT, Beal MF, Nathan C, Thomas B, Ding A (2010) Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J 24:4639-4647
187. Bailey KR, Rustay NR, Crawley JN (2006) Behavioral phenotyping of transgenic and knockout mice: practical concerns and potential pitfalls. ILAR J 47:124-131
188. Crawley JN, Belknap JK, Collins A, Crabbe JC, Frankel W, Henderson N, Hitzemann RJ, Maxson SC, Miner LL, Silva AJ, Wehner JM, Wynshaw-Boris A, Paylor R (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology (Berl) 132:107-124
189. Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, Rossi G, Pareyson D, Mole SE, Staropoli JF, Sims KB, Lewis J, Lin WL, Dickson DW, Dahl HH, Bahlo M, Berkovic SF (2012) Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet 90:1102-1107
190. Kohlschutter A, Schulz A (2009) Towards understanding the neuronal ceroid lipofuscinoses. Brain Dev 31:499-502
191. Kaye ED, Petrovic-Poljak A, Verhoeff NP, Freedman M (2010) Frontotemporal dementia and pharmacologic interventions. J Neuropsychiatry Clin Neurosci 22:19-29
192. Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, Bisceglio G, Rovelet-Lecrux A, Boeve B, Petersen RC, Dickson DW, Younkin SG, Deramecourt V, Crook J, Graff-Radford NR, Rademakers R (2009) Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain 132:583-591
193. Ghidoni R, Stoppani E, Rossi G, Piccoli E, Albertini V, Paterlini A, Glionna M, Pegoiani E, Agnati LF, Fenoglio C, Scarpini E, Galimberti D, Morbin M, Tagliavini F, Binetti G, Benussi L (2012) Optimal plasma progranulin cutoff value for predicting null progranulin mutations in neurodegenerative diseases: a multicenter Italian study. Neurodegener Dis 9:121-127
194. Sleegers K, Brouwers N, Van Damme P, Engelborghs S, Gijselinck I, van der Zee J, Peeters K, Mattheijssens M, Cruts M, Vandenberghe R, De Deyn PP, Robberecht W, Van Broeckhoven C (2009) A serum biomarker for progranulin-associated frontotemporal lobar degeneration. Ann Neurol 65:603-609
195. Tao J, Ji F, Wang F, Liu B, Zhu Y (2012) Neuroprotective effects of progranulin in ischemic mice. Brain Res 1436:130-136
196. Vossel KA, Miller BL (2008) New approaches to the treatment of frontotemporal lobar degeneration. Curr Opin Neurol 21:708-716
197. Du L, Damoiseaux R, Nahas S, Gao K, Hu H, Pollard JM, Goldstine J, Jung ME, Henning SM, Bertoni C, Gatti RA (2009) Nonaminoglycoside compounds induce readthrough of nonsense mutations. J Exp Med 206: 2285-2297. Doi: 10.1084/jem.20081940
198. Manuvakhova M, Keeling K, Bedwell DM (2000) Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system. RNA 6:1044-1055
199. Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature 447:87-91
200. Finkel RS (2010) Read-through strategies for suppression of nonsense mutations in Duchenne/Becker muscular dystrophy: aminoglycosides and ataluren (PTC124). J Child Neurol 25:1158-1164
201. Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL (2007) Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol 47:430-444
202. Cenik B, Sephton CF, Dewey CM, Xian X, Wei S, Yu K, Niu W, Coppola G, Coughlin SE, Lee SE, Dries DR, Almeida S, Geschwind DH, Gao FB, Miller BL, Farese RV Jr, Posner BA, Yu G, Herz J (2011) Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem 286:16101-16108
203. Capell A, Liebscher S, Fellerer K, Brouwers N, Willem M, Lammich S, Gijselinck I, Bittner T, Carlson AM, Sasse F, Kunze B, Steinmetz H, Jansen R, Dormann D, Sleegers K, Cruts M, Herms J, Van Broeckhoven C, Haass C (2011) Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase. J Neurosci 31:1885-1894
204. Almeida S, Zhou L, Gao FB (2011) Progranulin, a glycoprotein deficient in frontotemporal dementia, is a novel substrate of several protein disulfide isomerase family proteins. PLoS One 6:e26454
205. Kiser D, Steemers B, Branchi I, Homberg JR (2012) The reciprocal interaction between serotonin and social behaviour. Neurosci Biobehav Rev 36:786-798
206. Huey ED, Putnam KT, Grafman J (2006) A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology 66:17-22
207. Lebert F, Stekke W, Hasenbroekx C, Pasquier F (2004) Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord 17:355-359
208. Trojanowski JQ, Duff K, Fillit H, Koroshetz W, Kuret J, Murphy D, Refolo L (2008) New directions for frontotemporal dementia drug discovery. Alzheimers Dement 4:89-93
209. Galimberti D, Fenoglio C, Scarpini E (2008) Inflammation in neurodegenerative disorders: friend or foe? Curr Aging Sci 1:30-41
210. Nukiwa T, Suzuki T, Fukuhara T, Kikuchi T (2008) Secretory leukocyte peptidase inhibitor and lung cancer. Cancer Sci 99:849-855
211. Matayoshi H, Hirata T, Yamashita S, Ishida K, Mizukami Y, Gondo T, Matsumoto M, Sakabe T (2009) Neutrophil elastase inhibitor attenuates hippocampal neuronal damage after transient forebrain ischemia in rats. Brain Res 1259:98-106
212. Shimakura A, Kamanaka Y, Ikeda Y, Kondo K, Suzuki Y, Umemura K (2000) Neutrophil elastase inhibition reduces cerebral ischemic damage in the middle cerebral artery occlusion. Brain Res 858:55-60
213. Yamauchi T, Sawa Y, Sakurai M, Hiroshi T, Matsumiya G, Abe K, Matsuda H (2006) ONO-5046 attenuation of delayed motor neuron death and effect on the induction of brain-derived neurotrophic factor, phosphorylated extracellular signal-regulated kinase, and caspase3 after spinal cord ischemia in rabbits. J Thorac Cardiovasc Surg 131:644-650