Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration
2012; Elsevier BV; Volume: 287; Issue: 39 Linguagem: Inglês
10.1074/jbc.r112.399170
ISSN1083-351X
AutoresBasar Cenik, Chantelle F. Sephton, Bercin Kutluk Cenik, Joachim Herz, Gang Yu,
Tópico(s)Cholinesterase and Neurodegenerative Diseases
ResumoGRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration. GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration. Progranulin (encoded by GRN) is widely expressed in epithelia, bone marrow, immune cells, solid organs, and the nervous system both during development and in adulthood (1Bhandari V. Palfree R.G. Bateman A. Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains.Proc. Natl. Acad. Sci. 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Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration.Neurology. 2008; 71: 1235-1239Crossref PubMed Scopus (256) Google Scholar). Progranulin is evolutionarily conserved in Animalia: homologs exist in vertebrates and Caenorhabditis elegans (14Kao A.W. Eisenhut R.J. Martens L.H. Nakamura A. Huang A. Bagley J.A. Zhou P. de Luis A. Neukomm L.J. Cabello J. Farese Jr., R.V. Kenyon C. A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 4441-4446Crossref PubMed Scopus (94) Google Scholar), but seemingly not in Drosophila. It has no robust sequence homology to any other known protein family. Biological activities attributed to progranulin are numerous; the protein is made up of several granulin domains, which can be individually liberated by neutrophil proteases (see Fig. 1). These “granulins” were discovered first, before the cloning of the full-length gene. Whether the biological activities of progranulin are mediated by the full-length protein, individual granulins, or both is not clear. We begin our discussion with the consequences of progranulin deficiency. In 2006, mutations in GRN were discovered to be a cause of frontotemporal lobar degeneration (FTLD) 3The abbreviations used are: FTLDfrontotemporal lobar degenerationNCLneuronal ceroid lipofuscinosisTNFRTNF receptorSLPIsecretory leukocyte protease inhibitor. with ubiquitinated TDP-43-positive inclusions (FTLD-TDP) (15Baker M. Mackenzie I.R. Pickering-Brown S.M. Gass J. Rademakers R. Lindholm C. Snowden J. Adamson J. Sadovnick A.D. Rollinson S. Cannon A. Dwosh E. Neary D. Melquist S. Richardson A. Dickson D. Berger Z. Eriksen J. Robinson T. Zehr C. Dickey C.A. Crook R. McGowan E. Mann D. Boeve B. Feldman H. Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.Nature. 2006; 442: 916-919Crossref PubMed Scopus (1603) Google Scholar, 16Cruts M. Gijselinck I. van der Zee J. Engelborghs S. Wils H. Pirici D. Rademakers R. Vandenberghe R. Dermaut B. Martin J.J. van Duijn C. Peeters K. Sciot R. Santens P. De Pooter T. Mattheijssens M. Van den Broeck M. Cuijt I. Vennekens K. De Deyn P.P. Kumar-Singh S. Van Broeckhoven C. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.Nature. 2006; 442: 920-924Crossref PubMed Scopus (1235) Google Scholar). FTLD is the second most common presenile dementia disorder after Alzheimer disease, representing 5–15% of all dementias (17Ratnavalli E. Brayne C. Dawson K. Hodges J.R. The prevalence of frontotemporal dementia.Neurology. 2002; 58: 1615-1621Crossref PubMed Scopus (902) Google Scholar, 18Rabinovici G.D. Miller B.L. Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis, and management.CNS Drugs. 2010; 24: 375-398Crossref PubMed Scopus (287) Google Scholar). More than 70 mutations in GRN, almost all of which result in null alleles, have been identified in FTLD patients. A few causative missense mutations also result in reduced levels of progranulin (19Shankaran S.S. Capell A. Hruscha A.T. Fellerer K. Neumann M. Schmid B. Haass C. Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion.J. Biol. Chem. 2008; 283: 1744-1753Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). frontotemporal lobar degeneration neuronal ceroid lipofuscinosis TNF receptor secretory leukocyte protease inhibitor. Clinical manifestations of heterozygous loss-of-function GRN mutations include variants of the FTLD spectrum, parkinsonism, and the corticobasal syndrome (20van Swieten J.C. Heutink P. Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia.Lancet Neurol. 2008; 7: 965-974Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Neuropathologically, atrophy of the brain parenchyma (most severe in the frontal cortex) is usually observed. The atrophy can be asymmetrical, and different brain regions are affected with varying frequency. Loss of pigmentation of the substantia nigra, hippocampal sclerosis, and atrophy of temporal and parietal lobes are variably observed (20van Swieten J.C. Heutink P. Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia.Lancet Neurol. 2008; 7: 965-974Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). The characteristic cellular pathology is neuronal cytoplasmic inclusions and dystrophic neurites. These inclusions are positive for TDP-43, an RNA-binding protein and splicing modulator that binds GRN mRNA (21Sephton C.F. Cenik C. Kucukural A. Dammer E.B. Cenik B. Han Y. Dewey C.M. Roth F.P. Herz J. Peng J. Moore M.J. Yu G. Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes.J. Biol. Chem. 2011; 286: 1204-1215Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar, 22Colombrita C. Onesto E. Megiorni F. Pizzuti A. Baralle F.E. Buratti E. Silani V. Ratti A. TDP-43 and FUS RNA-binding proteins bind distinct sets of cytoplasmic messenger RNAs and differently regulate their post-transcriptional fate in motoneuron-like cells.J. Biol. Chem. 2012; 287: 15635-15647Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). TDP-43 protein in these inclusions is ubiquitinated and hyperphosphorylated and may be proteolytically processed (23Neumann M. Sampathu D.M. Kwong L.K. Truax A.C. Micsenyi M.C. Chou T.T. Bruce J. Schuck T. Grossman M. Clark C.M. McCluskey L.F. Miller B.L. Masliah E. Mackenzie I.R. Feldman H. Feiden W. Kretzschmar H.A. Trojanowski J.Q. Lee V.M. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Science. 2006; 314: 130-133Crossref PubMed Scopus (4471) Google Scholar). Loss of normal nuclear staining for TDP-43 is typical. Gliosis is also commonly observed (Table 1).TABLE 1Comparison of two diseases caused by GRN mutationsDiseaseFTLD-TDP with GRN mutationsNCL with GRN mutationGRN mutationsHeterozygous loss of function, >70 different mutations reportedHomozygous loss of function, c.813_816del (p.Thr272Serfs*10) reported in two siblingsMost common clinical presentationBehavioral changes, language dysfunctionVision loss, seizuresMacroscopic pathologySevere frontotemporal cortical atrophyCerebellar atrophyMicroscopic pathologyNeuronal loss and gliosis, neuronal cytoplasmic and intranuclear inclusions, dystrophic neurites, ubiquitinated phosphorylated TDP-43 aggregates“Fingerprint profiles” seen by EM in skin biopsy samples, brain pathology unknown Open table in a new tab In hereditary cases, the mode of inheritance is autosomal dominant with incomplete penetrance (24Gass J. Cannon A. Mackenzie I.R. Boeve B. Baker M. Adamson J. Crook R. Melquist S. Kuntz K. Petersen R. Josephs K. Pickering-Brown S.M. Graff-Radford N. Uitti R. Dickson D. Wszolek Z. Gonzalez J. Beach T.G. Bigio E. Johnson N. Weintraub S. Mesulam M. White 3rd, C.L. Woodruff B. Caselli R. Hsiung G.Y. Feldman H. Knopman D. Hutton M. Rademakers R. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.Hum. Mol. Genet. 2006; 15: 2988-3001Crossref PubMed Scopus (485) Google Scholar, 25Rademakers R. Baker M. Gass J. Adamson J. Huey E.D. Momeni P. Spina S. Coppola G. Karydas A.M. Stewart H. Johnson N. Hsiung G.Y. Kelley B. Kuntz K. Steinbart E. Wood E.M. Yu C.E. Josephs K. Sorenson E. Womack K.B. Weintraub S. Pickering-Brown S.M. Schofield P.R. Brooks W.S. Van Deerlin V.M. Snowden J. Clark C.M. Kertesz A. Boylan K. Ghetti B. Neary D. Schellenberg G.D. Beach T.G. Mesulam M. Mann D. Grafman J. Mackenzie I.R. Feldman H. Bird T. Petersen R. Knopman D. Boeve B. Geschwind D.H. Miller B. Wszolek Z. Lippa C. Bigio E.H. Dickson D. Graff-Radford N. Hutton M. 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Farese Jr., R.V. Posner B.A. Yu G. Herz J. Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia.J. Biol. Chem. 2011; 286: 16101-16108Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Two homozygous GRN-deficient patients have been recently reported (30Smith K.R. Damiano J. Franceschetti S. Carpenter S. Canafoglia L. Morbin M. Rossi G. Pareyson D. Mole S.E. Staropoli J.F. Sims K.B. Lewis J. Lin W.L. Dickson D.W. Dahl H.H. Bahlo M. Berkovic S.F. Strikingly different clinicopathological phenotypes determined by progranulin mutation dosage.Am. J. Hum. Genet. 2012; 90: 1102-1107Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar). These patients presented with adult onset neuronal ceroid lipofuscinosis (NCL), suffering from progressive loss of vision, retinal dystrophy, cerebellar ataxia, and seizures (Table 1). Circulating progranulin was undetectable. NCLs are genetic progressive lysosomal storage diseases characterized by accumulation of lipofuscin (31Kohlschütter A. Schulz A. Towards understanding the neuronal ceroid lipofuscinoses.Brain Dev. 2009; 31: 499-502Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). At least 10 related disorders are now classified as NCLs. Causative mutations occur in genes encoding lysosomal enzymes and several incompletely characterized membrane proteins. Lipofuscin is an aggregate of oxidized cross-linked proteins and lipids. It can be toxic to cells by chelating metals, enhancing oxidative damage, and inhibiting mitochondrial and lysosomal function (32Jung T. Bader N. Grune T. Lipofuscin: formation, distribution, and metabolic consequences.Ann. N.Y. Acad. Sci. 2007; 1119: 97-111Crossref PubMed Scopus (303) Google Scholar). Lipofuscin accumulation occurs during normal aging but is greatly accelerated in NCLs. Interestingly, increased accumulation of lipofuscin has not been reported in cases of FTLD-TDP but has been detected in mouse models of the disease (see below). Several independent mouse lines with genetic Grn deletions have been generated. Behaviorally, the most consistent finding is social interaction deficits (33Yin F. Dumont M. Banerjee R. Ma Y. Li H. Lin M.T. Beal M.F. Nathan C. Thomas B. Ding A. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia.FASEB J. 2010; 24: 4639-4647Crossref PubMed Scopus (134) Google Scholar, 34Ghoshal N. Dearborn J.T. Wozniak D.F. Cairns N.J. Core features of frontotemporal dementia recapitulated in progranulin knock-out mice.Neurobiol. Dis. 2012; 45: 395-408Crossref PubMed Scopus (81) Google Scholar, 35Petkau T.L. Neal S.J. Milnerwood A. Mew A. Hill A.M. Orban P. Gregg J. Lu G. Feldman H.H. Mackenzie I.R. Raymond L.A. Leavitt B.R. Synaptic dysfunction in progranulin-deficient mice.Neurobiol. Dis. 2012; 45: 711-722Crossref PubMed Scopus (117) Google Scholar). In a classic test of hippocampal learning and memory (Morris water maze), Grn−/− mice had mild deficits at old age (18–21 months) in two studies (33Yin F. Dumont M. Banerjee R. Ma Y. Li H. Lin M.T. Beal M.F. Nathan C. Thomas B. Ding A. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia.FASEB J. 2010; 24: 4639-4647Crossref PubMed Scopus (134) Google Scholar, 36Wils H. Kleinberger G. Pereson S. Janssens J. Capell A. Van Dam D. Cuijt I. Joris G. De Deyn P.P. Haass C. Van Broeckhoven C. Kumar-Singh S. Cellular ageing, increased mortality, and FTLD-TDP-associated neuropathology in progranulin knock-out mice.J. Pathol. 2012; 228: 67-76PubMed Google Scholar) but no deficits at 8 months of age in another study (35Petkau T.L. Neal S.J. Milnerwood A. Mew A. Hill A.M. Orban P. Gregg J. Lu G. Feldman H.H. Mackenzie I.R. Raymond L.A. Leavitt B.R. Synaptic dysfunction in progranulin-deficient mice.Neurobiol. Dis. 2012; 45: 711-722Crossref PubMed Scopus (117) Google Scholar). Other reported behavioral deficits include depression-like behavior and either increased (35Petkau T.L. Neal S.J. Milnerwood A. Mew A. Hill A.M. Orban P. Gregg J. Lu G. Feldman H.H. Mackenzie I.R. Raymond L.A. Leavitt B.R. Synaptic dysfunction in progranulin-deficient mice.Neurobiol. Dis. 2012; 45: 711-722Crossref PubMed Scopus (117) Google Scholar, 37Kayasuga Y. Chiba S. Suzuki M. Kikusui T. Matsuwaki T. Yamanouchi K. Kotaki H. Horai R. Iwakura Y. Nishihara M. Alteration of behavioral phenotype in mice by targeted disruption of the progranulin gene.Behav. Brain Res. 2007; 185: 110-118Crossref PubMed Scopus (141) Google Scholar) or decreased (33Yin F. Dumont M. Banerjee R. Ma Y. Li H. Lin M.T. Beal M.F. Nathan C. Thomas B. Ding A. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia.FASEB J. 2010; 24: 4639-4647Crossref PubMed Scopus (134) Google Scholar) anxiety. These behavioral phenotypes are fairly consistent with the clinical manifestations of FTLD, which include early behavioral problems and later deficits in memory. Histopathologically, robust microgliosis, astrogliosis, and increased ubiquitin staining are observed in the brains of aged Grn−/− mice (7Ahmed Z. Sheng H. Xu Y.F. Lin W.L. Innes A.E. Gass J. Yu X. Wuertzer C.A. Hou H. Chiba S. Yamanouchi K. Leissring M. Petrucelli L. Nishihara M. Hutton M.L. McGowan E. Dickson D.W. Lewis J. Accelerated lipofuscinosis and ubiquitination in granulin knock-out mice suggest a role for progranulin in successful aging.Am. J. Pathol. 2010; 177: 311-324Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 33Yin F. Dumont M. Banerjee R. Ma Y. Li H. Lin M.T. Beal M.F. Nathan C. Thomas B. Ding A. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia.FASEB J. 2010; 24: 4639-4647Crossref PubMed Scopus (134) Google Scholar, 34Ghoshal N. Dearborn J.T. Wozniak D.F. Cairns N.J. Core features of frontotemporal dementia recapitulated in progranulin knock-out mice.Neurobiol. Dis. 2012; 45: 395-408Crossref PubMed Scopus (81) Google Scholar, 35Petkau T.L. Neal S.J. Milnerwood A. Mew A. Hill A.M. Orban P. Gregg J. Lu G. Feldman H.H. Mackenzie I.R. Raymond L.A. Leavitt B.R. Synaptic dysfunction in progranulin-deficient mice.Neurobiol. Dis. 2012; 45: 711-722Crossref PubMed Scopus (117) Google Scholar, 38Yin F. Banerjee R. Thomas B. Zhou P. Qian L. Jia T. Ma X. Ma Y. Iadecola C. Beal M.F. Nathan C. Ding A. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice.J. Exp. Med. 2010; 207: 117-128Crossref PubMed Scopus (344) Google Scholar). Ahmed et al. (7Ahmed Z. Sheng H. Xu Y.F. Lin W.L. Innes A.E. Gass J. Yu X. Wuertzer C.A. Hou H. Chiba S. Yamanouchi K. Leissring M. Petrucelli L. Nishihara M. Hutton M.L. McGowan E. Dickson D.W. Lewis J. Accelerated lipofuscinosis and ubiquitination in granulin knock-out mice suggest a role for progranulin in successful aging.Am. J. Pathol. 2010; 177: 311-324Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar) recently showed that intracytoplasmic ubiquitinated aggregates observed in these mice are probably composed of lipofuscin. This finding was replicated in an independent Grn−/− line (36Wils H. Kleinberger G. Pereson S. Janssens J. Capell A. Van Dam D. Cuijt I. Joris G. De Deyn P.P. Haass C. Van Broeckhoven C. Kumar-Singh S. Cellular ageing, increased mortality, and FTLD-TDP-associated neuropathology in progranulin knock-out mice.J. Pathol. 2012; 228: 67-76PubMed Google Scholar). Although some vacuolation was observed in the habenula and hippocampus in very old (23 months) Grn−/− mice (7Ahmed Z. Sheng H. Xu Y.F. Lin W.L. Innes A.E. Gass J. Yu X. Wuertzer C.A. Hou H. Chiba S. Yamanouchi K. Leissring M. Petrucelli L. Nishihara M. Hutton M.L. McGowan E. Dickson D.W. Lewis J. Accelerated lipofuscinosis and ubiquitination in granulin knock-out mice suggest a role for progranulin in successful aging.Am. J. Pathol. 2010; 177: 311-324Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar), overt neuronal loss seems to be very mild or absent (34Ghoshal N. Dearborn J.T. Wozniak D.F. Cairns N.J. Core features of frontotemporal dementia recapitulated in progranulin knock-out mice.Neurobiol. Dis. 2012; 45: 395-408Crossref PubMed Scopus (81) Google Scholar), in contrast with the severe atrophy observed in human FTLD. Yin et al. (33Yin F. Dumont M. Banerjee R. Ma Y. Li H. Lin M.T. Beal M.F. Nathan C. Thomas B. Ding A. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia.FASEB J. 2010; 24: 4639-4647Crossref PubMed Scopus (134) Google Scholar) observed increased staining with an antibody against phosphorylated TDP-43 in the brains of 18-month-old Grn−/− mice; however, none of the other studies detected overt TDP-43 proteinopathy. Wils et al. (36Wils H. Kleinberger G. Pereson S. Janssens J. Capell A. Van Dam D. Cuijt I. Joris G. De Deyn P.P. Haass C. Van Broeckhoven C. Kumar-Singh S. Cellular ageing, increased mortality, and FTLD-TDP-associated neuropathology in progranulin knock-out mice.J. Pathol. 2012; 228: 67-76PubMed Google Scholar) recently reported somewhat increased phospho-TDP-43 immunoreactivity in detergent-insoluble fractions of Grn−/− mouse brains; nonetheless, they did not detect a significant difference in TDP-43 staining by immunohistochemistry. Interestingly, none of these findings were reported in heterozygous Grn+/− mice, which would be analogous to the haploinsufficient condition in human FTLD-TDP. Progranulin-deficient mice display dysregulated immune responses in the brain (38Yin F. Banerjee R. Thomas B. Zhou P. Qian L. Jia T. Ma X. Ma Y. Iadecola C. Beal M.F. Nathan C. Ding A. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice.J. Exp. Med. 2010; 207: 117-128Crossref PubMed Scopus (344) Google Scholar) Macrophages from Grn−/− mice express higher levels of proinflammatory cytokines (MCP-1, CXCL1, IL-6, IL-12p40, and TNF-α) in response to LPS, but they express less IL-10. Microglia cultured from these animals have toxic effects on co-cultured wild-type neurons. However, the immunomodulatory role of progranulin in the periphery may be different. In a recent study, Grn−/− mice on a high fat diet had reduced IL-6 concentrations in blood and adipose tissue. Interestingly, Grn ablation was protective against insulin resistance (5Matsubara T. Mita A. Minami K. Hosooka T. Kitazawa S. Takahashi K. Tamori Y. Yokoi N. Watanabe M. Matsuo E. Nishimura O. Seino S. PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue.Cell Metab. 2012; 15: 38-50Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Finally, loss of the progranulin homolog results in accelerated clearance of apoptotic cells in C. elegans (14Kao A.W. Eisenhut R.J. Martens L.H. Nakamura A. Huang A. Bagley J.A. Zhou P. de Luis A. Neukomm L.J. Cabello J. Farese Jr., R.V. Kenyon C. A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 4441-4446Crossref PubMed Scopus (94) Google Scholar) and disruption of motor neuron development in zebrafish (39Chitramuthu B.P. Baranowski D.C. Kay D.G. Bateman A. Bennett H.P. 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