Acta Neuropathologica

, Volume 127, Issue 6, pp 845–860 | Cite as

Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis

  • Julia K. Götzl
  • Kohji Mori
  • Markus Damme
  • Katrin Fellerer
  • Sabina Tahirovic
  • Gernot Kleinberger
  • Jonathan Janssens
  • Julie van der Zee
  • Christina M. Lang
  • Elisabeth Kremmer
  • Jean-Jacques Martin
  • Sebastiaan Engelborghs
  • Hans A. Kretzschmar
  • Thomas Arzberger
  • Christine Van Broeckhoven
  • Christian Haass
  • Anja Capell
Original Paper

Abstract

Heterozygous loss-of-function mutations in the progranulin (GRN) gene and the resulting reduction of GRN levels is a common genetic cause for frontotemporal lobar degeneration (FTLD) with accumulation of TAR DNA-binding protein (TDP)-43. Recently, it has been shown that a complete GRN deficiency due to a homozygous GRN loss-of-function mutation causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. These findings suggest that lysosomal dysfunction may also contribute to some extent to FTLD. Indeed, Grn(−/−) mice recapitulate not only pathobiochemical features of GRN-associated FTLD-TDP (FTLD-TDP/GRN), but also those which are characteristic for NCL and lysosomal impairment. In Grn(−/−) mice the lysosomal proteins cathepsin D (CTSD), LAMP (lysosomal-associated membrane protein) 1 and the NCL storage components saposin D and subunit c of mitochondrial ATP synthase (SCMAS) were all found to be elevated. Moreover, these mice display increased levels of transmembrane protein (TMEM) 106B, a lysosomal protein known as a risk factor for FTLD-TDP pathology. In line with a potential pathological overlap of FTLD and NCL, Ctsd(−/−) mice, a model for NCL, show elevated levels of the FTLD-associated proteins GRN and TMEM106B. In addition, pathologically phosphorylated TDP-43 occurs in Ctsd(−/−) mice to a similar extent as in Grn(−/−) mice. Consistent with these findings, some NCL patients accumulate pathologically phosphorylated TDP-43 within their brains. Based on these observations, we searched for pathological marker proteins, which are characteristic for NCL or lysosomal impairment in brains of FTLD-TDP/GRN patients. Strikingly, saposin D, SCMAS as well as the lysosomal proteins CTSD and LAMP1/2 are all elevated in patients with FTLD-TDP/GRN. Thus, our findings suggest that lysosomal storage disorders and GRN-associated FTLD may share common features.

Keywords

Frontotemporal lobar degeneration (FTLD) Progranulin (GRN) TDP-43 Neuronal ceroid lipofuscinosis (NCL) Cathepsin D Lysosome Neurodegeneration 

Supplementary material

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References

  1. 1.
    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(1):311–324. doi:10.2353/ajpath.2010.090915 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Amritraj A, Wang Y, Revett TJ, Vergote D, Westaway D, Kar S (2013) Role of cathepsin D in U18666A-induced neuronal cell death: potential implication in Niemann–Pick type C disease pathogenesis. J Biol Chem 288(5):3136–3152. doi:10.1074/jbc.M112.412460 PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    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(3):602–611. doi:10.1016/j.bbrc.2006.10.093 PubMedCrossRefGoogle Scholar
  4. 4.
    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(7105):916–919. doi:10.1038/nature05016 PubMedCrossRefGoogle Scholar
  5. 5.
    Benussi L, Binetti G, Sina E, Gigola L, Bettecken T, Meitinger T, Ghidoni R (2008) A novel deletion in progranulin gene is associated with FTDP-17 and CBS. Neurobiol Aging 29(3):427–435. doi:10.1016/j.neurobiolaging.2006.10.028 PubMedCrossRefGoogle Scholar
  6. 6.
    Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27(50):6434–6451. doi:10.1038/onc.2008.310 PubMedCrossRefGoogle Scholar
  7. 7.
    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(4):685–695. doi:10.1093/hmg/dds475 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    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(10):1436–1446. doi:10.1001/archneur.64.10.1436 PubMedCrossRefGoogle Scholar
  9. 9.
    Busch JI, Martinez-Lage M, Ashbridge E, Grossman M, Van Deerlin VM, Hu F, Lee VM, Trojanowski JQ, Chen-Plotkin AS (2013) Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain. Acta Neuropathol Commun 1(1):36PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Butler D, Hwang J, Estick C, Nishiyama A, Kumar SS, Baveghems C, Young-Oxendine HB, Wisniewski ML, Charalambides A, Bahr BA (2011) Protective effects of positive lysosomal modulation in Alzheimer’s disease transgenic mouse models. PLoS One 6(6):e20501. doi:10.1371/journal.pone.0020501 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    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(5):1885–1894. doi:10.1523/JNEUROSCI.5757-10.2011 PubMedCrossRefGoogle Scholar
  12. 12.
    Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, Lippa C, Nixon RA (1995) Gene expression and cellular content of cathepsin D in Alzheimer’s disease brain: evidence for early up-regulation of the endosomal-lysosomal system. Neuron 14(3):671–680PubMedCrossRefGoogle Scholar
  13. 13.
    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(33):11213–11227. doi:10.1523/JNEUROSCI.0521-12.2012 PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Cluzeau CV, Watkins-Chow DE, Fu R, Borate B, Yanjanin N, Dail MK, Davidson CD, Walkley SU, Ory DS, Wassif CA, Pavan WJ, Porter FD (2012) Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1. Hum Mol Genet 21(16):3632–3646. doi:10.1093/hmg/dds193 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    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(5):581–586. doi:10.1001/archneurol.2010.350 PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    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(7105):920–924. doi:10.1038/nature05017 PubMedCrossRefGoogle Scholar
  17. 17.
    Cruts M, Theuns J, Van Broeckhoven C (2012) Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 33(9):1340–1344. doi:10.1002/humu.22117 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Ebrahimi-Fakhari D, Wahlster L, McLean PJ (2012) Protein degradation pathways in Parkinson’s disease: curse or blessing. Acta Neuropathol 124(2):153–172. doi:10.1007/s00401-012-1004-6 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Elleder M, Sokolova J, Hrebicek M (1997) Follow-up study of subunit c of mitochondrial ATP synthase (SCMAS) in Batten disease and in unrelated lysosomal disorders. Acta Neuropathol 93(4):379–390PubMedCrossRefGoogle Scholar
  20. 20.
    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(Pt 3):583–591. doi:10.1093/brain/awn352 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    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(5):467–474. doi:10.1212/WNL.0b013e31820a0e3b PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Fritchie K, Siintola E, Armao D, Lehesjoki AE, Marino T, Powell C, Tennison M, Booker JM, Koch S, Partanen S, Suzuki K, Tyynela J, Thorne LB (2009) Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). Acta Neuropathol 117(2):201–208. doi:10.1007/s00401-008-0426-7 PubMedCrossRefGoogle Scholar
  23. 23.
    Gallagher MD, Suh E, Grossman M, Elman L, McCluskey L, Van Swieten JC, Al-Sarraj S, Neumann M, Gelpi E, Ghetti B, Rohrer JD, Halliday G, Van Broeckhoven C, Seilhean D, Shaw PJ, Frosch MP, Alafuzoff I, Antonell A, Bogdanovic N, Brooks W, Cairns NJ, Cooper-Knock J, Cotman C, Cras P, Cruts M, De Deyn PP, Decarli C, Dobson-Stone C, Engelborghs S, Fox N, Galasko D, Gearing M, Gijselinck I, Grafman J, Hartikainen P, Hatanpaa KJ, Highley JR, Hodges J, Hulette C, Ince PG, Jin LW, Kirby J, Kofler J, Kril J, Kwok JB, Levey A, Lieberman A, Llado A, Martin JJ, Masliah E, McDermott CJ, McKee A, McLean C, Mead S, Miller CA, Miller J, Munoz DG, Murrell J, Paulson H, Piguet O, Rossor M, Sanchez-Valle R, Sano M, Schneider J, Silbert LC, Spina S, van der Zee J, Van Langenhove T, Warren J, Wharton SB, White Iii CL, Woltjer RL, Trojanowski JQ, Lee VM, Van Deerlin V, Chen-Plotkin AS (2014) TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 127(3):407–418. doi:10.1007/s00401-013-1239-x PubMedCentralPubMedGoogle Scholar
  24. 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 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(20):2988–3001. doi:10.1093/hmg/ddl241 PubMedCrossRefGoogle Scholar
  25. 25.
    Ghidoni R, Benussi L, Glionna M, Franzoni M, Binetti G (2008) Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration. Neurology 71(16):1235–1239. doi:10.1212/01.wnl.0000325058.10218.fc PubMedCrossRefGoogle Scholar
  26. 26.
    Ghoshal N, Dearborn JT, Wozniak DF, Cairns NJ (2012) Core features of frontotemporal dementia recapitulated in progranulin knockout mice. Neurobiol Dis 45(1):395–408. doi:10.1016/j.nbd.2011.08.029 PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Gijselinck I, Van Broeckhoven C, Cruts M (2008) Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update. Hum Mutat 29(12):1373–1386. doi:10.1002/humu.20785 PubMedCrossRefGoogle Scholar
  28. 28.
    Graff-Radford NR, Woodruff BK (2007) Frontotemporal dementia. Semin Neurol 27(1):48–57. doi:10.1055/s-2006-956755 PubMedCrossRefGoogle Scholar
  29. 29.
    Hall NA, Lake BD, Dewji NN, Patrick AD (1991) Lysosomal storage of subunit c of mitochondrial ATP synthase in Batten’s disease (ceroid-lipofuscinosis). Biochem J 275(Pt 1):269–272PubMedCentralPubMedGoogle Scholar
  30. 30.
    Harris H, Rubinsztein DC (2012) Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol 8(2):108–117. doi:10.1038/nrneurol.2011.200 CrossRefGoogle Scholar
  31. 31.
    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(1):60–70. doi:10.1002/ana.21425 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    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(1):17–24. doi:10.1006/abbi.1997.9958 PubMedCrossRefGoogle Scholar
  33. 33.
    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(4):654–667. doi:10.1016/j.neuron.2010.09.034 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Jabs S, Quitsch A, Kakela R, Koch B, Tyynela J, Brade H, Glatzel M, Walkley S, Saftig P, Vanier MT, Braulke T (2008) Accumulation of bis(monoacylglycero)phosphate and gangliosides in mouse models of neuronal ceroid lipofuscinosis. J Neurochem 106(3):1415–1425. doi:10.1111/j.1471-4159.2008.05497.x PubMedCrossRefGoogle Scholar
  35. 35.
    Jalanko A, Braulke T (2009) Neuronal ceroid lipofuscinoses. Biochim Biophys Acta 1793(4):697–709. doi:10.1016/j.bbamcr.2008.11.004 PubMedCrossRefGoogle Scholar
  36. 36.
    Janssens J, Van Broeckhoven C (2013) Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders. Hum Mol Genet. doi:10.1093/hmg/ddt349 PubMedCentralPubMedGoogle Scholar
  37. 37.
    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(2):110–118. doi:10.1016/j.bbr.2007.07.020 PubMedCrossRefGoogle Scholar
  38. 38.
    Klein A, Henseler M, Klein C, Suzuki K, Harzer K, Sandhoff K (1994) Sphingolipid activator protein D (sap-D) stimulates the lysosomal degradation of ceramide in vivo. Biochem Biophys Res Commun 200(3):1440–1448. doi:10.1006/bbrc.1994.1612 PubMedCrossRefGoogle Scholar
  39. 39.
    Koike M, Nakanishi H, Saftig P, Ezaki J, Isahara K, Ohsawa Y, Schulz-Schaeffer W, Watanabe T, Waguri S, Kametaka S, Shibata M, Yamamoto K, Kominami E, Peters C, von Figura K, Uchiyama Y (2000) Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J Neurosci 20(18):6898–6906PubMedGoogle Scholar
  40. 40.
    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(23):19355–19365. doi:10.1074/jbc.M112.365098 PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    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, French research network on FF-M (2008) Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain 131(Pt 3):732–746. doi:10.1093/brain/awn012 PubMedCrossRefGoogle Scholar
  42. 42.
    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 for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117(1):15–18. doi:10.1007/s00401-008-0460-5 PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    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 (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119(1):1–4. doi:10.1007/s00401-009-0612-2 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Martin JJ, Ceuterick C (1997) Adult neuronal ceroid-lipofuscinosis—personal observations. Acta Neurol Belg 97(2):85–92PubMedGoogle Scholar
  45. 45.
    Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, Haass C, Edbauer D (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339(6125):1335–1338. doi:10.1126/science.1232927 PubMedCrossRefGoogle Scholar
  46. 46.
    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(4):512–521. doi:10.1002/humu.20681 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Nakanishi H, Zhang J, Koike M, Nishioku T, Okamoto Y, Kominami E, von Figura K, Peters C, Yamamoto K, Saftig P, Uchiyama Y (2001) Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice. J Neurosci 21(19):7526–7533PubMedGoogle Scholar
  48. 48.
    Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, Forman MS, Troost D, Kretzschmar HA, Trojanowski JQ, Lee VM (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117(2):137–149. doi:10.1007/s00401-008-0477-9 PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    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(5796):130–133. doi:10.1126/science.1134108 PubMedCrossRefGoogle Scholar
  50. 50.
    Nijssen PC, Ceuterick C, van Diggelen OP, Elleder M, Martin JJ, Teepen JL, Tyynela J, Roos RA (2003) Autosomal dominant adult neuronal ceroid lipofuscinosis: a novel form of NCL with granular osmiophilic deposits without palmitoyl protein thioesterase 1 deficiency. Brain Pathol 13(4):574–581PubMedCrossRefGoogle Scholar
  51. 51.
    Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19(8):983–997. doi:10.1038/nm.3232 PubMedCrossRefGoogle Scholar
  52. 52.
    Nixon RA, Yang DS (2011) Autophagy failure in Alzheimer’s disease-locating the primary defect. Neurobiol Dis 43(1):38–45. doi:10.1016/j.nbd.2011.01.021 PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Partanen S, Haapanen A, Kielar C, Pontikis C, Alexander N, Inkinen T, Saftig P, Gillingwater TH, Cooper JD, Tyynela J (2008) Synaptic changes in the thalamocortical system of cathepsin D-deficient mice: a model of human congenital neuronal ceroid-lipofuscinosis. J Neuropathol Exp Neurol 67(1):16–29. doi:10.1097/nen.0b013e31815f3899 PubMedCrossRefGoogle Scholar
  54. 54.
    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(2):711–722. doi:10.1016/j.nbd.2011.10.016 PubMedCrossRefGoogle Scholar
  55. 55.
    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(19):3931–3947. doi:10.1002/cne.22430 PubMedCrossRefGoogle Scholar
  56. 56.
    Qiao L, Hamamichi S, Caldwell KA, Caldwell GA, Yacoubian TA, Wilson S, Xie ZL, Speake LD, Parks R, Crabtree D, Liang Q, Crimmins S, Schneider L, Uchiyama Y, Iwatsubo T, Zhou Y, Peng L, Lu Y, Standaert DG, Walls KC, Shacka JJ, Roth KA, Zhang J (2008) Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol Brain 1:17. doi:10.1186/1756-6606-1-17 PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Repnik U, Stoka V, Turk V, Turk B (2012) Lysosomes and lysosomal cathepsins in cell death. Biochim Biophys Acta 1824(1):22–33. doi:10.1016/j.bbapap.2011.08.016 PubMedCrossRefGoogle Scholar
  58. 58.
    Rubinsztein DC (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443(7113):780–786. doi:10.1038/nature05291 PubMedCrossRefGoogle Scholar
  59. 59.
    Ryazantsev S, Yu WH, Zhao HZ, Neufeld EF, Ohmi K (2007) Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B. Mol Genet Metab 90(4):393–401. doi:10.1016/j.ymgme.2006.11.006 PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, Koster A, Hess B, Evers M, von Figura K et al (1995) Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J 14(15):3599–3608PubMedCentralPubMedGoogle Scholar
  61. 61.
    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(5939):473–477. doi:10.1126/science.1174447 PubMedGoogle Scholar
  62. 62.
    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(5):476–486. doi:10.1136/jnnp.2010.212225 PubMedCrossRefGoogle Scholar
  63. 63.
    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(3):1744–1753. doi:10.1074/jbc.M705115200 PubMedCrossRefGoogle Scholar
  64. 64.
    Sieben A, Van Langenhove T, Engelborghs S, Martin JJ, Boon P, Cras P, De Deyn PP, Santens P, Van Broeckhoven C, Cruts M (2012) The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 124(3):353–372. doi:10.1007/s00401-012-1029-x PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J, Lehesjoki AE, Tyynela J (2006) Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129(Pt 6):1438–1445. doi:10.1093/brain/awl107 PubMedCrossRefGoogle Scholar
  66. 66.
    Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, Hummerich H, Nielsen JE, Hodges JR, Spillantini MG, Thusgaard T, Brandner S, Brun A, Rossor MN, Gade A, Johannsen P, Sorensen SA, Gydesen S, Fisher EM, Collinge J (2005) Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 37(8):806–808. doi:10.1038/ng1609 PubMedCrossRefGoogle Scholar
  67. 67.
    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) Serum biomarker for progranulin-associated frontotemporal lobar degeneration. Ann Neurol 65(5):603–609. doi:10.1002/ana.21621 PubMedCrossRefGoogle Scholar
  68. 68.
    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(6):1102–1107. doi:10.1016/j.ajhg.2012.04.021 PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    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. doi:10.1016/j.neuroscience.2012.11.032 PubMedCrossRefGoogle Scholar
  70. 70.
    Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M (2013) Increased lysosomal biogenesis in activated microglia and exacerbated neuronal damage after traumatic brain injury in progranulin-deficient mice. Neuroscience 250C:8–19. doi:10.1016/j.neuroscience.2013.06.049 CrossRefGoogle Scholar
  71. 71.
    Tofaris GK (2012) Lysosome-dependent pathways as a unifying theme in Parkinson’s disease. Mov Disord 27(11):1364–1369. doi:10.1002/mds.25136 PubMedCrossRefGoogle Scholar
  72. 72.
    Tresse E, Salomons FA, Vesa J, Bott LC, Kimonis V, Yao TP, Dantuma NP, Taylor JP (2010) VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6(2):217–227PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Tyynela J, Palmer DN, Baumann M, Haltia M (1993) Storage of saposins A and D in infantile neuronal ceroid-lipofuscinosis. FEBS Lett 330(1):8–12PubMedCrossRefGoogle Scholar
  74. 74.
    Urwin H, Authier A, Nielsen JE, Metcalf D, Powell C, Froud K, Malcolm DS, Holm I, Johannsen P, Brown J, Fisher EM, van der Zee J, Bruyland M, Consortium FR, Van Broeckhoven C, Collinge J, Brandner S, Futter C, Isaacs AM (2010) Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. Hum Mol Genet 19(11):2228–2238. doi:10.1093/hmg/ddq100 PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    van Blitterswijk M, Mullen B, Nicholson AM, Bieniek KF, Heckman MG, Baker MC, Dejesus-Hernandez M, Finch NA, Brown PH, Murray ME, Hsiung GY, Stewart H, Karydas AM, Finger E, Kertesz A, Bigio EH, Weintraub S, Mesulam M, Hatanpaa KJ, White Iii CL, Strong MJ, Beach TG, Wszolek ZK, Lippa C, Caselli R, Petrucelli L, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Mackenzie IR, Seeley WW, Grinberg LT, Miller BL, Boylan KB, Graff-Radford NR, Boeve BF, Dickson DW, Rademakers R (2014) TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 127(3):397–406. doi:10.1007/s00401-013-1240-4 PubMedGoogle Scholar
  76. 76.
    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(3):234–239. doi:10.1038/ng.536 PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    van der Zee J, Le Ber I, Maurer-Stroh S, Engelborghs S, Gijselinck I, Camuzat A, Brouwers N, Vandenberghe R, Sleegers K, Hannequin D, Dermaut B, Schymkowitz J, Campion D, Santens P, Martin JJ, Lacomblez L, De Pooter T, Peeters K, Mattheijssens M, Vercelletto M, Van den Broeck M, Cruts M, De Deyn PP, Rousseau F, Brice A, Van Broeckhoven C (2007) Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia. Hum Mutat 28(4):416. doi:10.1002/humu.9484 PubMedGoogle Scholar
  78. 78.
    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(Pt 3):808–815. doi:10.1093/brain/awr007 PubMedCentralPubMedGoogle Scholar
  79. 79.
    Vitner EB, Dekel H, Zigdon H, Shachar T, Farfel-Becker T, Eilam R, Karlsson S, Futerman AH (2010) Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses. Hum Mol Genet 19(18):3583–3590. doi:10.1093/hmg/ddq273 PubMedCrossRefGoogle Scholar
  80. 80.
    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(5):1305–1315. doi:10.1111/j.1471-4159.2009.06546.x PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Watts GD, Thomasova D, Ramdeen SK, Fulchiero EC, Mehta SG, Drachman DA, Weihl CC, Jamrozik Z, Kwiecinski H, Kaminska A, Kimonis VE (2007) Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. Clin Genet 72(5):420–426. doi:10.1111/j.1399-0004.2007.00887.x PubMedCrossRefGoogle Scholar
  82. 82.
    Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36(4):377–381. doi:10.1038/ng1332 PubMedCrossRefGoogle Scholar
  83. 83.
    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. doi:10.1002/path.4043 PubMedGoogle Scholar
  84. 84.
    Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, Schmidt SD, Wesson D, Bandyopadhyay U, Jiang Y, Pawlik M, Peterhoff CM, Yang AJ, Wilson DA, St George-Hyslop P, Westaway D, Mathews PM, Levy E, Cuervo AM, Nixon RA (2011) Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain 134(Pt 1):258–277. doi:10.1093/brain/awq341 PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    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(1):117–128. doi:10.1084/jem.20091568 PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    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(12):4639–4647. doi:10.1096/fj.10-161471 PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Yu CE, Bird TD, Bekris LM, Montine TJ, Leverenz JB, Steinbart E, Galloway NM, Feldman H, Woltjer R, Miller CA, Wood EM, Grossman M, McCluskey L, Clark CM, Neumann M, Danek A, Galasko DR, Arnold SE, Chen-Plotkin A, Karydas A, Miller BL, Trojanowski JQ, Lee VM, Schellenberg GD, Van Deerlin VM (2010) The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol 67(2):161–170. doi:10.1001/archneurol.2009.328 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Julia K. Götzl
    • 1
    • 2
  • Kohji Mori
    • 1
  • Markus Damme
    • 3
  • Katrin Fellerer
    • 1
  • Sabina Tahirovic
    • 4
  • Gernot Kleinberger
    • 1
    • 6
    • 7
    • 5
  • Jonathan Janssens
    • 6
    • 7
  • Julie van der Zee
    • 6
    • 7
  • Christina M. Lang
    • 1
  • Elisabeth Kremmer
    • 4
    • 8
  • Jean-Jacques Martin
    • 7
  • Sebastiaan Engelborghs
    • 7
  • Hans A. Kretzschmar
    • 9
  • Thomas Arzberger
    • 4
    • 9
    • 10
  • Christine Van Broeckhoven
    • 6
    • 7
  • Christian Haass
    • 1
    • 4
    • 5
  • Anja Capell
    • 1
  1. 1.Adolf-Butenandt Institute, BiochemistryLudwig-Maximilians-University MunichMunichGermany
  2. 2.Institute of NeuroscienceTechnical University MunichMunichGermany
  3. 3.Department of BiochemistryChristian-Albrechts-University KielKielGermany
  4. 4.German Center for Neurodegenerative Diseases (DZNE) MunichMunichGermany
  5. 5.Munich Cluster for Systems Neurology (SyNergy)MunichGermany
  6. 6.Department of Molecular GeneticsNeurodegenerative Brain Disease GroupAntwerpBelgium
  7. 7.Institute Born-BungeUniversity of AntwerpAntwerpBelgium
  8. 8.Institute of Molecular ImmunologyHelmholtz Center Munich, German Research Center for Environmental Health (GmbH)MunichGermany
  9. 9.Center for Neuropathology and Prion ResearchLudwig-Maximilians-University MunichMunichGermany
  10. 10.Department of Psychiatry and PsychotherapyLudwig-Maximilians-University MunichMunichGermany

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