Skip to main content

Advertisement

SpringerLink
Log in

The lysosomal function of progranulin, a guardian against neurodegeneration

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Progranulin (PGRN), encoded by the GRN gene in humans, is a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing and tumorigenesis. The clinical importance of PGRN became especially evident in 2006, when heterozygous mutations in the GRN gene, resulting in haploinsufficiency, were found to be one of the main causes of frontotemporal lobar degeneration (FTLD). FTLD is a clinically heterogenous disease that results in the progressive atrophy of the frontal and temporal lobes of the brain. Despite significant research, the exact function of PGRN and its mechanistic relationship to FTLD remain unclear. However, growing evidence suggests a role for PGRN in the lysosome—most striking being that homozygous GRN mutation leads to neuronal ceroid lipofuscinosis, a lysosomal storage disease. Since this discovery, several links between PGRN and the lysosome have been established, including the existence of two independent lysosomal trafficking pathways, intralysosomal processing of PGRN into discrete functional peptides, and direct and indirect regulation of lysosomal hydrolases. Here, we summarize the cellular functions of PGRN, its roles in the nervous system, and its link to multiple neurodegenerative diseases, with a particular focus dedicated to recent lysosome-related mechanistic developments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

3′-UTR:

3'-untranslated region

Aβ:

Amyloid-β

AD:

Alzheimer’s disease

ADAMTS-7:

A disintegrin and metalloproteinase with thrombospondin motifs 7

ALS:

Amyotrophic lateral sclerosis

C9orf72:

Chromosome 9 open reading frame 72

CHMP2B:

Charged multivesicular body protein 2B

CI-M6PR:

Cation-independent mannose-6-phosphate receptor

CLN11:

Ceroid lipofuscinosis, neuronal 11

CPPIC:

Cysteine protease of protease-inhibitor complex

CTSD:

Cathepsin D

CTSL:

Cathepsin L

EphA2:

EPH receptor A2

ESCRT-III:

Endosomal sorting complexes required for transport-III

FTD:

Frontotemporal dementia

FTLD:

Frontotemporal lobar degeneration

FTLD-FUS:

FTLD with fused in sarcoma protein-positive inclusions

FTLD-GRN :

FTLD with GRN mutation

FTLD-TAU:

FTLD with tau-positive inclusions

FTLD-TDP:

FTLD with TAR DNA-binding protein 43-positive inclusions

GBA:

Glucocerebrosidase

GD:

Gaucher disease

GEP:

Granulin–epithelin precursor

GWAS:

Genome-wide association study

Hsp70:

Heat shock protein 70

iPSC:

Induced pluripotent stem cell

LIMP-2:

Lysosome membrane protein 2

LRP1:

Low-density lipoprotein receptor-related protein 1

LSD:

Lysosomal storage disease

MAP6:

Microtubule-associated protein 6

MAPT:

Microtubule-associated protein tau

NCL:

Neuronal ceroid lipofuscinosis

OPTN:

Optineurin

PCDGF:

PC cell-derived growth factor

PD:

Parkinson’s disease

PEPI:

Proepithelin

PGRN:

Progranulin

PNFA:

Progressive nonfluent aphasia

PPA:

Primary progressive aphasia

proNGF:

Nerve growth factor precursor

PSAP:

Prosaposin

RD21:

Responsive-to-desiccation-21

SD:

Semantic dementia

SQSTM1:

Sequestosome 1

SNP:

Single-nucleotide polymorphism

TBK1:

TANK-binding kinase 1

TDP-43:

TAR DNA-binding protein 43

TFEB:

Transcription factor EB

TGN:

Trans-Golgi network

TNF:

Tumor necrosis factor

Trem2:

Triggering receptor expressed on myeloid cells 2

VCP:

Valosin-containing protein

References

  1. Abrhale T, Brodie A, Sabnis G, Macedo L, Tian C, Yue B, Serrero G (2011) GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells. BMC Cancer 11:231. https://doi.org/10.1186/1471-2407-11-231

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Ahmed Z, Sheng H, Xu YF, Lin WL, Innes AE, Gass J, Yu X, Wuertzer CA, 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 suggest a role for progranulin in successful aging. Am J Pathol 177:311–324. https://doi.org/10.2353/ajpath.2010.090915

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Almeida MR, Macario MC, Ramos L, Baldeiras I, Ribeiro MH, Santana I (2016) Portuguese family with the co-occurrence of frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis phenotypes due to progranulin gene mutation. Neurobiol Aging 41(200):e201–e205. https://doi.org/10.1016/j.neurobiolaging.2016.02.019

    Article  CAS  Google Scholar 

  4. 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. https://doi.org/10.1371/journal.pone.0026454

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Altmann C, Vasic V, Hardt S, Heidler J, Haussler A, Wittig I, Schmidt MH, Tegeder I (2016) Progranulin promotes peripheral nerve regeneration and reinnervation: role of notch signaling. Mol Neurodegener 11:69. https://doi.org/10.1186/s13024-016-0132-1

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Arechavaleta-Velasco F, Perez-Juarez CE, Gerton GL, Diaz-Cueto L (2017) Progranulin and its biological effects in cancer. Med Oncol 34:194. https://doi.org/10.1007/s12032-017-1054-7

    Article  CAS  PubMed  Google Scholar 

  7. 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. https://doi.org/10.1128/MCB.00056-09

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. 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

    Article  CAS  Google Scholar 

  9. Baladron V, Ruiz-Hidalgo MJ, Bonvini E, Gubina E, Notario V, Laborda J (2002) The EGF-like homeotic protein dlk affects cell growth and interacts with growth-modulating molecules in the yeast two-hybrid system. Biochem Biophys Res Commun 291:193–204. https://doi.org/10.1006/bbrc.2002.6431

    Article  CAS  PubMed  Google Scholar 

  10. 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. https://doi.org/10.1016/S0006-291X(05)80908-8

    Article  CAS  PubMed  Google Scholar 

  11. Beel S, Moisse M, Damme M, De Muynck L, Robberecht W, Van Den Bosch L, Saftig P, Van Damme P (2017) Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo. Hum Mol Genet. https://doi.org/10.1093/hmg/ddx162

    Article  PubMed Central  PubMed  Google Scholar 

  12. Belcastro V, Siciliano V, Gregoretti F, Mithbaokar P, Dharmalingam G, Berlingieri S, Iorio F, Oliva G, Polishchuck R, Brunetti-Pierri N, di Bernardo D (2011) Transcriptional gene network inference from a massive dataset elucidates transcriptome organization and gene function. Nucl Acids Res 39:8677–8688. https://doi.org/10.1093/nar/gkr593

    Article  CAS  PubMed  Google Scholar 

  13. Beutler E, Demina A, Gelbart T (1994) Glucocerebrosidase mutations in Gaucher disease. Mol Med 1:82–92

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Beutler E, Grabowski G (1995) Guacher disease. The metabolic basis of inherited disease, 7th edn. McGraw-Hill, New York

    Google Scholar 

  15. 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  CAS  Google Scholar 

  16. Brady OA, Zheng Y, Murphy K, Huang M, Hu F (2013) The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet 22:685–695. https://doi.org/10.1093/hmg/dds475

    Article  CAS  PubMed  Google Scholar 

  17. Busch JI, Unger TL, Jain N, Tyler Skrinak R, Charan RA, Chen-Plotkin AS (2016) Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Hum Mol Genet 25:2681–2697. https://doi.org/10.1093/hmg/ddw127

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. 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. https://doi.org/10.1128/MCB.01775-07

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. 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. https://doi.org/10.1016/j.ajhg.2010.11.002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G (2012) Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem 287:32298–32306. https://doi.org/10.1074/jbc.R112.399170

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Chang MC, Srinivasan K, Friedman BA, Suto E, Modrusan Z, Lee WP, Kaminker JS, Hansen DV, Sheng M (2017) Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation. J Exp Med 214:2611–2628. https://doi.org/10.1084/jem.20160999

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L, Busch JI, Akle S, Grossman M, Van Deerlin V, 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. https://doi.org/10.1523/JNEUROSCI.0521-12.2012

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Chen LW, Yung KK, Chan YS, Shum DK, Bolam JP (2008) The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson’s disease. CNS Neurol Disord Drug Targets 7:512–523

    Article  CAS  Google Scholar 

  24. Chen X, Chang J, Deng Q, Xu J, Nguyen TA, Martens LH, Cenik B, Taylor G, Hudson KF, Chung J, Yu K, Yu P, Herz J, Farese RV Jr, Kukar T, Tansey MG (2013) Progranulin does not bind tumor necrosis factor (TNF) receptors and is not a direct regulator of TNF-dependent signaling or bioactivity in immune or neuronal cells. J Neurosci 33:9202–9213. https://doi.org/10.1523/JNEUROSCI.5336-12.2013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. 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. https://doi.org/10.1186/1750-1326-5-41

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Cotman SL, Karaa A, Staropoli JF, Sims KB (2013) Neuronal ceroid lipofuscinosis: impact of recent genetic advances and expansion of the clinicopathologic spectrum. Curr Neurol Neurosci Rep 13:366. https://doi.org/10.1007/s11910-013-0366-z

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. 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

    Article  CAS  Google Scholar 

  28. 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  CAS  Google Scholar 

  29. De Muynck L, Herdewyn S, Beel S, Scheveneels W, Van Den Bosch L, Robberecht W, Van Damme P (2013) The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding. Neurobiol Aging 34:2541–2547. https://doi.org/10.1016/j.neurobiolaging.2013.04.022

    Article  CAS  PubMed  Google Scholar 

  30. Dicou E, Vincent JP, Mazella J (2004) Neurotensin receptor-3/sortilin mediates neurotensin-induced cytokine/chemokine expression in a murine microglial cell line. J Neurosci Res 78:92–99

    Article  CAS  Google Scholar 

  31. Edelman MJ, Feliciano J, Yue B, Bejarano P, Ioffe O, Reisman D, Hawkins D, Gai Q, Hicks D, Serrero G (2014) GP88 (progranulin): a novel tissue and circulating biomarker for non-small cell lung carcinoma. Hum Pathol 45:1893–1899. https://doi.org/10.1016/j.humpath.2014.05.011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Evers BM, Rodriguez-Navas C, Tesla RJ, Prange-Kiel J, Wasser CR, Yoo KS, McDonald J, Cenik B, Ravenscroft TA, Plattner F, Rademakers R, Yu G, White CL 3rd, Herz J (2017) Lipidomic and transcriptomic basis of lysosomal dysfunction in progranulin deficiency. Cell Rep 20:2565–2574. https://doi.org/10.1016/j.celrep.2017.08.056

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M, Crook R, Hunter T, Ghidoni R, Benussi L, Crook J, Finger E, Hantanpaa KJ, Karydas AM, Sengdy P, Gonzalez J, Seeley WW, Johnson N, Beach TG, Mesulam M, Forloni G, Kertesz A, Knopman DS, Uitti R, White CL 3rd, Caselli R, Lippa C, Bigio EH, Wszolek ZK, Binetti G, Mackenzie IR, Miller BL, Boeve BF, Younkin SG, Dickson DW, Petersen RC, Graff-Radford NR, Geschwind DH, Rademakers R (2011) TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 76:467–474. https://doi.org/10.1212/WNL.0b013e31820a0e3b

    Article  CAS  PubMed  Google Scholar 

  34. 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. https://doi.org/10.1007/s13238-010-0067-1

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. 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 3rd, 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

    Article  CAS  Google Scholar 

  36. 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. https://doi.org/10.1186/1750-1326-7-33

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Gonzalez EM, Mongiat M, Slater SJ, Baffa R, Iozzo RV (2003) A novel interaction between perlecan protein core and progranulin: potential effects on tumor growth. J Biol Chem 278:38113–38116

    Article  CAS  Google Scholar 

  38. Gopalakrishnan MM, Grosch HW, Locatelli-Hoops S, Werth N, Smolenova E, Nettersheim M, Sandhoff K, Hasilik A (2004) Purified recombinant human prosaposin forms oligomers that bind procathepsin D and affect its autoactivation. Biochem J 383:507–515. https://doi.org/10.1042/BJ20040175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Gotzl JK, Mori K, Damme M, Fellerer K, Tahirovic S, Kleinberger G, Janssens J, van der Zee J, Lang CM, Kremmer E, Martin JJ, Engelborghs S, Kretzschmar HA, Arzberger T, Van Broeckhoven C, Haass C, Capell A (2014) Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 127:845–860. https://doi.org/10.1007/s00401-014-1262-6

    Article  CAS  PubMed  Google Scholar 

  40. Gowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, De Camilli P, Ferguson SM (2015) Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques. Proc Natl Acad Sci USA 112:E3699–E3708. https://doi.org/10.1073/pnas.1510329112

    Article  CAS  PubMed  Google Scholar 

  41. Gu C, Shabab M, Strasser R, Wolters PJ, Shindo T, Niemer M, Kaschani F, Mach L, van der Hoorn RA (2012) Post-translational regulation and trafficking of the granulin-containing protease RD21 of Arabidopsis thaliana. PLoS One 7:e32422. https://doi.org/10.1371/journal.pone.0032422

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. 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

    Article  CAS  Google Scholar 

  43. He Z, Ismail A, Kriazhev L, Sadvakassova G, Bateman A (2002) Progranulin (PC-cell-derived growth factor/acrogranin) regulates invasion and cell survival. Cancer Res 62:5590–5596

    CAS  PubMed  Google Scholar 

  44. He Z, Ong CH, Halper J, Bateman A (2003) Progranulin is a mediator of the wound response. Nat Med 9:225–229

    Article  CAS  Google Scholar 

  45. Hiraiwa M, Martin BM, Kishimoto Y, Conner GE, Tsuji S, O’Brien JS (1997) Lysosomal proteolysis of prosaposin, the precursor of saposins (sphingolipid activator proteins): its mechanism and inhibition by ganglioside. Arch Biochem Biophys 341:17–24. https://doi.org/10.1006/abbi.1997.9958

    Article  CAS  PubMed  Google Scholar 

  46. Holler CJ, Taylor G, Deng Q, Kukar T (2017) Intracellular proteolysis of progranulin generates stable, lysosomal granulins that are haploinsufficient in patients with frontotemporal dementia caused by GRN mutations. Eneuro. https://doi.org/10.1523/ENEURO.0100-17.2017

    Article  PubMed Central  PubMed  Google Scholar 

  47. Hosokawa M, Tanaka Y, Arai T, Kondo H, Akiyama H, Hasegawa M (2018) Progranulin haploinsufficiency reduces amyloid beta deposition in Alzheimer’s disease model mice. Exp Anim 67:63–70. https://doi.org/10.1538/expanim.17-0060

    Article  PubMed  Google Scholar 

  48. 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

    Article  CAS  Google Scholar 

  49. Hsiung GY, Fok A, Feldman HH, Rademakers R, Mackenzie IR (2011) rs5848 polymorphism and serum progranulin level. J Neurol Sci 300:28–32. https://doi.org/10.1016/j.jns.2010.10.009

    Article  CAS  PubMed  Google Scholar 

  50. 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. https://doi.org/10.1016/j.neuron.2010.09.034

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Jian J, Konopka J, Liu C (2013) Insights into the role of progranulin in immunity, infection, and inflammation. J Leukoc Biol 93:199–208. https://doi.org/10.1189/jlb.0812429

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Jian J, Tian QY, Hettinghouse A, Zhao S, Liu H, Wei J, Grunig G, Zhang W, Setchell KDR, Sun Y, Overkleeft HS, Chan GL, Liu CJ (2016) Progranulin recruits HSP70 to beta-glucocerebrosidase and is therapeutic against gaucher disease. EBioMedicine 13:212–224. https://doi.org/10.1016/j.ebiom.2016.10.010

    Article  PubMed Central  PubMed  Google Scholar 

  53. Jian J, Zhao S, Tian QY, Liu H, Zhao Y, Chen WC, Grunig G, Torres PA, Wang BC, Zeng B, Pastores G, Tang W, Sun Y, Grabowski GA, Kong MX, Wang G, Chen Y, Liang F, Overkleeft HS, Saunders-Pullman R, Chan GL, Liu CJ (2016) Association between progranulin and gaucher disease. EBioMedicine 11:127–137. https://doi.org/10.1016/j.ebiom.2016.08.004

    Article  PubMed Central  PubMed  Google Scholar 

  54. Jun MH, Han JH, Lee YK, Jang DJ, Kaang BK, Lee JA (2015) TMEM106B, a frontotemporal lobar dementia (FTLD) modifier, associates with FTD-3-linked CHMP2B, a complex of ESCRT-III. Mol Brain 8:85. https://doi.org/10.1186/s13041-015-0177-z

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Kamalainen A, Viswanathan J, Natunen T, Helisalmi S, Kauppinen T, Pikkarainen M, Pursiheimo JP, Alafuzoff I, Kivipelto M, Haapasalo A, Soininen H, Herukka SK, Hiltunen M (2013) GRN variant rs5848 reduces plasma and brain levels of granulin in Alzheimer’s disease patients. J Alzheimers Dis 33:23–27. https://doi.org/10.3233/JAD-2012-120946

    Article  CAS  PubMed  Google Scholar 

  56. Kao AW, Eisenhut RJ, Martens LH, Nakamura A, Huang A, Bagley JA, Zhou P, de Luis A, 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 USA 108:4441–4446. https://doi.org/10.1073/pnas.1100650108

    Article  CAS  PubMed  Google Scholar 

  57. Kao AW, McKay A, Singh PP, Brunet A, Huang EJ (2017) Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci 18:325–333. https://doi.org/10.1038/nrn.2017.36

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. 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

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Klein ZA, Takahashi H, Ma M, Stagi M, Zhou M, Lam TT, Strittmatter SM (2017) Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related phenotypes in progranulin-deficient mice. Neuron 95(281–296):e286. https://doi.org/10.1016/j.neuron.2017.06.026

    Article  CAS  Google Scholar 

  60. Kohlschutter A, Schulz A (2009) Towards understanding the neuronal ceroid lipofuscinoses. Brain Dev 31:499–502. https://doi.org/10.1016/j.braindev.2008.12.008

    Article  PubMed  Google Scholar 

  61. Kojima Y, Ono K, Inoue K, Takagi Y, Kikuta K, Nishimura M, Yoshida Y, Nakashima Y, Matsumae H, Furukawa Y, Mikuni N, Nobuyoshi M, Kimura T, Kita T, Tanaka M (2009) Progranulin expression in advanced human atherosclerotic plaque. Atherosclerosis 206:102–108. https://doi.org/10.1016/j.atherosclerosis.2009.02.017

    Article  CAS  PubMed  Google Scholar 

  62. 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. https://doi.org/10.1371/journal.pone.0013368

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Lang CM, Fellerer K, Schwenk BM, Kuhn PH, Kremmer E, Edbauer D, Capell A, Haass C (2012) Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. J Biol Chem 287:19355–19365. https://doi.org/10.1074/jbc.M112.365098

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Laurent-Matha V, Lucas A, Huttler S, Sandhoff K, Garcia M, Rochefort H (2002) Procathepsin D interacts with prosaposin in cancer cells but its internalization is not mediated by LDL receptor-related protein. Exp Cell Res 277:210–219

    Article  CAS  Google Scholar 

  65. Lee CW, Stankowski JN, Chew J, Cook CN, Lam YW, Almeida S, Carlomagno Y, Lau KF, Prudencio M, Gao FB, Bogyo M, Dickson DW, Petrucelli L (2017) The lysosomal protein cathepsin L is a progranulin protease. Mol Neurodegener 12:55. https://doi.org/10.1186/s13024-017-0196-6

    Article  PubMed Central  PubMed  Google Scholar 

  66. Lee MJ, Chen TF, Cheng TW, Chiu MJ (2011) rs5848 variant of progranulin gene is a risk of Alzheimer’s disease in the Taiwanese population. Neurodegener Dis 8:216–220. https://doi.org/10.1159/000322538

    Article  CAS  PubMed  Google Scholar 

  67. Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59:1077–1079

    Article  Google Scholar 

  68. 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 USA 98:142–147

    Article  CAS  Google Scholar 

  69. Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW, Huang HY, Shang Y, Oldham MC, Martens LH, Gao F, Coppola G, Sloan SA, Hsieh CL, Kim CC, Bigio EH, Weintraub S, Mesulam MM, Rademakers R, Mackenzie IR, Seeley WW, Karydas A, Miller BL, Borroni B, Ghidoni R, Farese RV Jr, Paz JT, Barres BA, Huang EJ (2016) Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell. https://doi.org/10.1016/j.cell.2016.04.001

    Article  PubMed Central  PubMed  Google Scholar 

  70. Mackenzie IR, Baker M, Pickering-Brown S, Hsiung GY, Lindholm C, Dwosh E, Gass J, Cannon A, Rademakers R, Hutton M, Feldman HH (2006) The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 129:3081–3090

    Article  Google Scholar 

  71. Mackenzie IR, Neumann M (2016) Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies. J Neurochem 138(Suppl 1):54–70. https://doi.org/10.1111/jnc.13588

    Article  CAS  PubMed  Google Scholar 

  72. 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. https://doi.org/10.1172/JCI63113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Mazella J, Zsurger N, Navarro V, Chabry J, Kaghad M, Caput D, Ferrara P, Vita N, Gully D, Maffrand JP, Vincent JP (1998) The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J Biol Chem 273:26273–26276

    Article  CAS  Google Scholar 

  74. Minami SS, Min SW, Krabbe G, Wang C, Zhou Y, Asgarov R, Li Y, Martens LH, Elia LP, Ward ME, Mucke L, Farese RV Jr, Gan L (2014) Progranulin protects against amyloid beta deposition and toxicity in Alzheimer’s disease mouse models. Nat Med 20:1157–1164. https://doi.org/10.1038/nm.3672

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Moisse K, Volkening K, Leystra-Lantz C, Welch I, Hill T, Strong MJ (2009) Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury. Brain Res 1249:202–211. https://doi.org/10.1016/j.brainres.2008.10.021

    Article  CAS  PubMed  Google Scholar 

  76. Mole SE, Cotman SL (2015) Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta 1852:2237–2241. https://doi.org/10.1016/j.bbadis.2015.05.011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Morimoto S, Kishimoto Y, Tomich J, Weiler S, Ohashi T, Barranger JA, Kretz KA, O’Brien JS (1990) Interaction of saposins, acidic lipids, and glucosylceramidase. J Biol Chem 265:1933–1937

    CAS  PubMed  Google Scholar 

  78. Morimoto S, Martin BM, Yamamoto Y, Kretz KA, O’Brien JS, Kishimoto Y (1989) Saposin A: second cerebrosidase activator protein. Proc Natl Acad Sci USA 86:3389–3393

    Article  CAS  Google Scholar 

  79. 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 Grinberg L, 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

    Article  PubMed Central  CAS  Google Scholar 

  80. Nabar NR, Kehrl JH (2017) The Transcription factor EB links cellular stress to the immune response. Yale J Biol Med 90:301–315

    PubMed Central  PubMed  Google Scholar 

  81. Naphade SB, Kigerl KA, Jakeman LB, Kostyk SK, Popovich PG, Kuret J (2010) Progranulin expression is upregulated after spinal contusion in mice. Acta Neuropathol 119:123–133. https://doi.org/10.1007/s00401-009-0616-y

    Article  CAS  PubMed  Google Scholar 

  82. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554

    Article  CAS  Google Scholar 

  83. Neill T, Buraschi S, Goyal A, Sharpe C, Natkanski E, Schaefer L, Morrione A, Iozzo RV (2016) EphA2 is a functional receptor for the growth factor progranulin. J Cell Biol 215:687–703. https://doi.org/10.1083/jcb.201603079

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Nicholson AM, Finch NA, Almeida M, Perkerson RB, van Blitterswijk M, Wojtas A, Cenik B, Rotondo S, Inskeep V, Almasy L, Dyer T, Peralta J, Jun G, Wood AR, Frayling TM, Fuchsberger C, Fowler S, Teslovich TM, Manning AK, Kumar S, Curran J, Lehman D, Abecasis G, Duggirala R, Pottier C, Zahir HA, Crook JE, Karydas A, Mitic L, Sun Y, Dickson DW, Bu G, Herz J, Yu G, Miller BL, Ferguson S, Petersen RC, Graff-Radford N, Blangero J, Rademakers R (2016) Prosaposin is a regulator of progranulin levels and oligomerization. Nat Commun 7:11992. https://doi.org/10.1038/ncomms11992

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Nicholson AM, Finch NA, Wojtas A, Baker MC, Perkerson RB 3rd, Castanedes-Casey M, Rousseau L, Benussi L, Binetti G, Ghidoni R, Hsiung GY, Mackenzie IR, Finger E, Boeve BF, Ertekin-Taner N, Graff-Radford NR, Dickson DW, Rademakers R (2013) TMEM106B p. T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. J Neurochem 126:781–791. https://doi.org/10.1111/jnc.12329

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Nita DA, Mole SE, Minassian BA (2016) Neuronal ceroid lipofuscinoses. Epileptic Disord 18:73–88. https://doi.org/10.1684/epd.2016.0844

    Article  PubMed  Google Scholar 

  87. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427:843–848

    Article  CAS  Google Scholar 

  88. O’Brien JS, Kishimoto Y (1991) Saposin proteins: structure, function, and role in human lysosomal storage disorders. FASEB J 5:301–308

    Article  Google Scholar 

  89. 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

    Article  CAS  Google Scholar 

  90. Palfree RG, Bennett HP, Bateman A (2015) The evolution of the secreted regulatory protein progranulin. PLoS One 10:e0133749. https://doi.org/10.1371/journal.pone.0133749

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. 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. https://doi.org/10.1016/j.immuni.2011.01.018

    Article  CAS  PubMed  Google Scholar 

  92. 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

    Article  CAS  Google Scholar 

  93. 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. https://doi.org/10.1016/j.nbd.2011.10.016

    Article  CAS  PubMed  Google Scholar 

  94. 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. https://doi.org/10.1097/NEN.0b013e3181fc9aea

    Article  CAS  PubMed  Google Scholar 

  95. 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. https://doi.org/10.1016/j.ajpath.2010.11.002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. 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

    CAS  PubMed  Google Scholar 

  97. Pottier C, Ravenscroft TA, Sanchez-Contreras M, Rademakers R (2016) Genetics of FTLD: overview and what else we can expect from genetic studies. J Neurochem. https://doi.org/10.1111/jnc.13622

    Article  PubMed  Google Scholar 

  98. 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. https://doi.org/10.1093/hmg/ddn257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002) The prevalence of frontotemporal dementia. Neurology 58:1615–1621

    Article  CAS  Google Scholar 

  100. Rhinn H, Abeliovich A (2017) Differential aging analysis in human cerebral cortex identifies variants in TMEM106B and GRN that regulate aging phenotypes. Cell Syst 4(404–415):e405. https://doi.org/10.1016/j.cels.2017.02.009

    Article  CAS  Google Scholar 

  101. Roberson ED (2012) Mouse models of frontotemporal dementia. Ann Neurol 72:837–849. https://doi.org/10.1002/ana.23722

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. 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. https://doi.org/10.1016/j.neuron.2011.07.021

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. 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. https://doi.org/10.1186/1471-2202-10-130

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Salazar DA, Butler VJ, Argouarch AR, Hsu TY, Mason A, Nakamura A, McCurdy H, Cox D, Ng R, Pan G, Seeley WW, Miller BL, Kao AW (2015) The progranulin cleavage products, granulins, exacerbate TDP-43 toxicity and increase TDP-43 levels. J Neurosci Off J Soc Neurosci 35:9315–9328. https://doi.org/10.1523/JNEUROSCI.4808-14.2015

    Article  CAS  Google Scholar 

  105. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, Banfi S, Parenti G, Cattaneo E, Ballabio A (2009) A gene network regulating lysosomal biogenesis and function. Science 325:473–477. https://doi.org/10.1126/science.1174447

    Article  CAS  PubMed  Google Scholar 

  106. Schapira AH (2015) Glucocerebrosidase and Parkinson disease: recent advances. Mol Cell Neurosci 66:37–42. https://doi.org/10.1016/j.mcn.2015.03.013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Schwenk BM, Lang CM, Hogl S, Tahirovic S, Orozco D, Rentzsch K, Lichtenthaler SF, Hoogenraad CC, Capell A, Haass C, Edbauer D (2014) The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J. https://doi.org/10.1002/embj.201385857

    Article  PubMed Central  PubMed  Google Scholar 

  108. Schymick JC, Yang Y, Andersen PM, Vonsattel JP, Greenway M, Momeni P, Elder J, Chio A, Restagno G, Robberecht W, Dahlberg C, Mukherjee O, Goate A, Graff-Radford N, Caselli RJ, Hutton M, Gass J, Cannon A, Rademakers R, Singleton AB, Hardiman O, Rothstein J, Hardy J, Traynor BJ (2007) Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes. J Neurol Neurosurg Psychiatry 78:754–756

    Article  PubMed Central  CAS  Google Scholar 

  109. Serrero G, Hawkins DM, Yue B, Ioffe O, Bejarano P, Phillips JT, Head JF, Elliott RL, Tkaczuk KR, Godwin AK, Weaver J, Kim WE (2012) Progranulin (GP88) tumor tissue expression is associated with increased risk of recurrence in breast cancer patients diagnosed with estrogen receptor positive invasive ductal carcinoma. Br Cancer Res 14:R26. https://doi.org/10.1186/bcr3111

    Article  CAS  Google Scholar 

  110. Shacka JJ, Roth KA (2007) Cathepsin D deficiency and NCL/Batten disease: there’s more to death than apoptosis. Autophagy 3:474–476

    Article  CAS  Google Scholar 

  111. Sheng J, Su L, Xu Z, Chen G (2014) Progranulin polymorphism rs5848 is associated with increased risk of Alzheimer’s disease. Gene 542:141–145. https://doi.org/10.1016/j.gene.2014.03.041

    Article  CAS  PubMed  Google Scholar 

  112. 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 USA 87:7912–7916

    Article  CAS  Google Scholar 

  113. Simons C, Dyment D, Bent SJ, Crawford J, D’Hooghe M, Kohlschutter A, Venkateswaran S, Helman G, Poll-The BT, Makowski CC, Ito Y, Kernohan K, Hartley T, Waisfisz Q, Taft RJ, van der Knaap MS, Wolf NI (2017) A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. Brain 140:3105–3111. https://doi.org/10.1093/brain/awx314

    Article  PubMed  Google Scholar 

  114. 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. https://doi.org/10.1016/j.ajhg.2012.04.021

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  115. Snowden JS, Pickering-Brown SM, Mackenzie IR, Richardson AM, Varma A, Neary D, Mann DM (2006) Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 129:3091–3102

    Article  CAS  Google Scholar 

  116. 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. https://doi.org/10.1016/j.jprot.2010.02.013

    Article  CAS  PubMed  Google Scholar 

  117. Stagi M, Klein ZA, Gould TJ, Bewersdorf J, Strittmatter SM (2014) Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B. Mol Cell Neurosci 61:226–240. https://doi.org/10.1016/j.mcn.2014.07.006

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. 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. https://doi.org/10.1371/journal.pone.0035115

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Takahashi H, Klein ZA, Bhagat SM, Kaufman AC, Kostylev MA, Ikezu T, Strittmatter SM (2017) Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network. Acta Neuropathol 133:785–807. https://doi.org/10.1007/s00401-017-1668-z

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  120. Tanaka Y, Chambers JK, Matsuwaki T, Yamanouchi K, Nishihara M (2014) Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice. Acta Neuropathol Commun 2:78. https://doi.org/10.1186/s40478-014-0078-x

    Article  PubMed Central  PubMed  Google Scholar 

  121. Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M (2013) Exacerbated inflammatory responses related to activated microglia after traumatic brain injury in progranulin-deficient mice. Neuroscience 231:49–60. https://doi.org/10.1016/j.neuroscience.2012.11.032

    Article  CAS  PubMed  Google Scholar 

  122. 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. https://doi.org/10.1126/science.1199214

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Tangkeangsirisin W, Hayashi J, Serrero G (2004) PC cell-derived growth factor mediates tamoxifen resistance and promotes tumor growth of human breast cancer cells. Cancer Res 64:1737–1743

    Article  CAS  Google Scholar 

  124. Tangkeangsirisin W, Serrero G (2004) PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells. Carcinogenesis 25:1587–1592

    Article  CAS  Google Scholar 

  125. Toh H, Cao M, Daniels E, Bateman A (2013) Expression of the growth factor progranulin in endothelial cells influences growth and development of blood vessels: a novel mouse model. PLoS One 8:e64989. https://doi.org/10.1371/journal.pone.0064989

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. 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. https://doi.org/10.1007/s12031-011-9569-4

    Article  CAS  PubMed  Google Scholar 

  127. 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

    Article  PubMed Central  CAS  Google Scholar 

  128. Tolkatchev D, Ng A, Vranken W, Ni F (2000) Design and solution structure of a well-folded stack of two beta-hairpins based on the amino-terminal fragment of human granulin A. Biochemistry 39:2878–2886

    Article  CAS  Google Scholar 

  129. Tolkatchev D, Xu P, Ni F (2001) A peptide derived from the C-terminal part of a plant cysteine protease folds into a stack of two beta-hairpins, a scaffold present in the emerging family of granulin-like growth factors. J Pept Res 57:227–233. https://doi.org/10.1111/j.1399-3011.2001.00828

    Article  CAS  PubMed  Google Scholar 

  130. Uesaka N, Abe M, Konno K, Yamazaki M, Sakoori K, Watanabe T, Kao TH, Mikuni T, Watanabe M, Sakimura K, Kano M (2018) Retrograde signaling from progranulin to sort1 counteracts synapse elimination in the developing cerebellum. Neuron 97(796–805):e795. https://doi.org/10.1016/j.neuron.2018.01.018

    Article  CAS  Google Scholar 

  131. Valdez C, Wong YC, Schwake M, Bu G, Wszolek ZK, Krainc D (2017) Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients. Hum Mol Genet 26:4861–4872. https://doi.org/10.1093/hmg/ddx364

    Article  CAS  PubMed  Google Scholar 

  132. 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. https://doi.org/10.1083/jcb.200712039

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. 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 3rd, Ferrer I, Llado A, Neumann M, Kretzschmar HA, Hulette CM, Welsh-Bohmer KA, Miller BL, Alzualde A, Lopez de Munain A, 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. https://doi.org/10.1038/ng.536

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  134. Van Kampen JM, Kay DG (2017) Progranulin gene delivery reduces plaque burden and synaptic atrophy in a mouse model of Alzheimer’s disease. PLoS One 12:e0182896. https://doi.org/10.1371/journal.pone.0182896

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Vass R, Ashbridge E, Geser F, Hu WT, Grossman M, Clay-Falcone D, Elman L, McCluskey L, Lee VM, Van Deerlin VM, Trojanowski JQ, Chen-Plotkin AS (2011) Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta Neuropathol 121:373–380. https://doi.org/10.1007/s00401-010-0782-y

    Article  PubMed  Google Scholar 

  136. Vidoni C, Follo C, Savino M, Melone MA, Isidoro C (2016) The role of cathepsin D in the pathogenesis of human neurodegenerative disorders. Med Res Rev. https://doi.org/10.1002/med.21394

    Article  PubMed  Google Scholar 

  137. Vranken WF, Chen ZG, Xu P, James S, Bennett HP, Ni F (1999) A 30-residue fragment of the carp granulin-1 protein folds into a stack of two beta-hairpins similar to that found in the native protein. J Pept Res 53:590–597

    Article  CAS  Google Scholar 

  138. 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. https://doi.org/10.1111/j.1471-4159.2009.06546.x

    Article  CAS  PubMed  Google Scholar 

  139. Ward ME, Chen R, Huang HY, Ludwig C, Telpoukhovskaia M, Taubes A, Boudin H, Minami SS, Reichert M, Albrecht P, Gelfand JM, Cruz-Herranz A, Cordano C, Alavi MV, Leslie S, Seeley WW, Miller BL, Bigio E, Mesulam MM, Bogyo MS, Mackenzie IR, Staropoli JF, Cotman SL, Huang EJ, Gan L, Green AJ (2017) Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aah5642

    Article  PubMed Central  PubMed  Google Scholar 

  140. 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 228:67–76. https://doi.org/10.1002/path.4043

    Article  CAS  PubMed  Google Scholar 

  141. 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. Molecular & cellular proteomics: MCP 7:2215–2228. https://doi.org/10.1074/mcp.M800095-MCP200

    Article  CAS  PubMed  Google Scholar 

  142. Xu HM, Tan L, Wan Y, Tan MS, Zhang W, Zheng ZJ, Kong LL, Wang ZX, Jiang T, Yu JT (2017) PGRN is associated with late-onset Alzheimer’s disease: a case–control replication study and meta-analysis. Mol Neurobiol 54:1187–1195. https://doi.org/10.1007/s12035-016-9698-4

    Article  CAS  PubMed  Google Scholar 

  143. Xu K, Zhang Y, Ilalov K, Carlson CS, Feng JQ, Di Cesare PE, Liu CJ (2007) Cartilage oligomeric matrix protein associates with granulin–epithelin precursor (GEP) and potentiates GEP-stimulated chondrocyte proliferation. J Biol Chem 282:11347–11355

    Article  CAS  Google Scholar 

  144. Yamada K, Matsushima R, Nishimura M, Hara-Nishimura I (2001) A slow maturation of a cysteine protease with a granulin domain in the vacuoles of senescing Arabidopsis leaves. Plant Physiol 127:1626–1634

    Article  PubMed Central  CAS  Google Scholar 

  145. Yamada T, Kondo A, Ohta H, Masuda T, Shimada H, Takamiya K (2001) Isolation of the protease component of maize cysteine protease–cystatin complex: release of cystatin is not crucial for the activation of the cysteine protease. Plant Cell Physiol 42:710–716

    Article  CAS  Google Scholar 

  146. Yamada T, Ohta H, Masuda T, Ikeda M, Tomita N, Ozawa A, Shioi Y, Takamiya K (1998) Purification of a novel type of SDS-dependent protease in maize using a monoclonal antibody. Plant Cell Physiol 39:106–114

    Article  CAS  Google Scholar 

  147. Yamamoto Y, Goto N, Takemura M, Yamasuge W, Yabe K, Takami T, Miyazaki T, Takeuchi T, Shiraki M, Shimizu M, Adachi S, Saito K, Shibata Y, Nakamura N, Hara T, Serrero G, Tsurumi H (2017) Association between increased serum GP88 (progranulin) concentrations and prognosis in patients with malignant lymphomas. Clin Chim Acta 473:139–146. https://doi.org/10.1016/j.cca.2017.07.024

    Article  CAS  PubMed  Google Scholar 

  148. Yan H, Kubisiak T, Ji H, Xiao J, Wang J, Burmeister M (2018) The recurrent mutation in TMEM106B also causes hypomyelinating leukodystrophy in China and is a CpG hot spot. Brain. https://doi.org/10.1093/brain/awy029

    Article  PubMed  Google Scholar 

  149. Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T, Ma X, Ma Y, Iadecola C, Beal MF, Nathan C, Ding A (2010) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 207:117–128. https://doi.org/10.1084/jem.20091568

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  150. 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. https://doi.org/10.1096/fj.10-161471

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  151. 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

    CAS  PubMed  Google Scholar 

  152. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, Deng S, Liddelow SA, Zhang C, Daneman R, Maniatis T, Barres BA, Wu JQ (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci Off J Soc Neurosci 34:11929–11947. https://doi.org/10.1523/JNEUROSCI.1860-14.2014

    Article  CAS  Google Scholar 

  153. 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. https://doi.org/10.1371/journal.pone.0021023

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  154. Zhou X, Paushter DH, Feng T, Pardon CM, Mendoza CS, Hu F (2017) Regulation of cathepsin D activity by the FTLD protein progranulin. Acta Neuropathol 134:151–153. https://doi.org/10.1007/s00401-017-1719-5

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  155. Zhou X, Paushter DH, Feng T, Sun L, Reinheckel T, Hu F (2017) Lysosomal processing of progranulin. Mol Neurodegener 12:62. https://doi.org/10.1186/s13024-017-0205-9

    Article  PubMed Central  PubMed  Google Scholar 

  156. Zhou X, Sullivan PM, Sun L, Hu F (2017) The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C. J Neurochem. https://doi.org/10.1111/jnc.14110

    Article  PubMed  Google Scholar 

  157. Zhou X, Sun L, Bastos de Oliveira F, Qi X, Brown WJ, Smolka MB, Sun Y, Hu F (2015) Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol 210:991–1002. https://doi.org/10.1083/jcb.201502029

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  158. Zhou X, Sun L, Bracko O, Choi JW, Jia Y, Nana AL, Brady OA, Hernandez JCC, Nishimura N, Seeley WW, Hu F (2017) Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. Nat Commun 8:15277. https://doi.org/10.1038/ncomms15277

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  159. Zhou X, Sun L, Brady OA, Murphy KA, Hu F (2017) Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency. Acta Neuropathol Commun 5:9. https://doi.org/10.1186/s40478-017-0412-1

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  160. 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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported by funding to F.H. from NINDS (R01NS088448, R01NS095954).

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, 345 Weill Hall, Ithaca, NY, 14853, USA

    Daniel H. Paushter, Huan Du, Tuancheng Feng & Fenghua Hu

Authors
  1. Daniel H. Paushter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huan Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tuancheng Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fenghua Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fenghua Hu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Paushter, D.H., Du, H., Feng, T. et al. The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathol 136, 1–17 (2018). https://doi.org/10.1007/s00401-018-1861-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-018-1861-8

Keywords

Search

Navigation