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Molecular Neurodegeneration

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Open Access 01-12-2017 | Short report

Lysosomal processing of progranulin

Authors: Xiaolai Zhou, Daniel H. Paushter, Tuancheng Feng, Lirong Sun, Thomas Reinheckel, Fenghua Hu

Published in: Molecular Neurodegeneration | Issue 1/2017

Abstract

Background

Mutations resulting in progranulin (PGRN) haploinsufficiency cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. PGRN is localized to the lysosome and important for proper lysosome function. However, the metabolism of PGRN in the lysosome is still unclear.

Results

Here, we report that PGRN is processed into ~10 kDa peptides intracellularly in multiple cell types and tissues and this processing is dependent on lysosomal activities. PGRN endocytosed from the extracellular space is also processed in a similar manner. We further demonstrated that multiple cathepsins are involved in PGRN processing and cathepsin L cleaves PGRN in vitro.

Conclusions

Our data support that PGRN is processed in the lysosome through the actions of cathepsins.

Ahmed Z, Mackenzie IR, Hutton ML, Dickson DW. Progranulin in frontotemporal lobar degeneration and neuroinflammation. J Neuroinflammation. 2007;4:7. https://doi.org/10.1186/1742-2094-4-7.CrossRefPubMedPubMedCentral

Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem. 2012;287(39):32298–306. https://doi.org/10.1074/jbc.R112.399170.CrossRefPubMedPubMedCentral

Bateman A, Bennett HP. The granulin gene family: from cancer to dementia. BioEssays. 2009;31(11):1245–54. https://doi.org/10.1002/bies.200900086.CrossRefPubMed

Nicholson AM, Gass J, Petrucelli L, Rademakers R. Progranulin axis and recent developments in frontotemporal lobar degeneration. Alzheimers Res Ther. 2012;4(1):4. doi:alzrt102 [pii]. https://doi.org/10.1186/alzrt102.CrossRefPubMedPubMedCentral

Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51(6):1546–54.CrossRefPubMed

Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, et al. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet. 2012;90(6):1102–7. https://doi.org/10.1016/j.ajhg.2012.04.021.CrossRefPubMedPubMedCentral

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

Belcastro V, Siciliano V, Gregoretti F, Mithbaokar P, Dharmalingam G, Berlingieri S, et al. Transcriptional gene network inference from a massive dataset elucidates transcriptome organization and gene function. Nucleic Acids Res. 2011;39(20):8677–88. https://doi.org/10.1093/nar/gkr593.CrossRefPubMedPubMedCentral

Hu F, Padukkavidana T, Vaegter CB, Brady OA, Zheng Y, Mackenzie IR, et al. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron. 2010;68(4):654–67. https://doi.org/10.1016/j.neuron.2010.09.034.CrossRefPubMedPubMedCentral

10.

Zhou X, Sun L, Bastos de Oliveira F, Qi X, Brown WJ, Smolka MB, et al. Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol. 2015;210(6):991–1002. https://doi.org/10.1083/jcb.201502029.CrossRefPubMedPubMedCentral

11.

O'Brien JS, Kishimoto Y. Saposin proteins: structure, function, and role in human lysosomal storage disorders. FASEB J. 1991;5(3):301–8.PubMed

12.

Qi X, Grabowski GA. Molecular and cell biology of acid beta-glucosidase and prosaposin. Prog Nucleic Acid Res Mol Biol. 2001;66:203–39.CrossRefPubMed

13.

Matsuda J, Yoneshige A, Suzuki K. The function of sphingolipids in the nervous system: lessons learnt from mouse models of specific sphingolipid activator protein deficiencies. J Neurochem. 2007;103(Suppl 1):32–8. https://doi.org/10.1111/j.1471-4159.2007.04709.x.CrossRefPubMed

14.

Zhu J, Nathan C, Jin W, Sim D, Ashcroft GS, Wahl SM, et al. Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell. 2002;111(6):867–78.CrossRefPubMed

15.

Suh HS, Choi N, Tarassishin L, Lee SC. Regulation of progranulin expression in human microglia and proteolysis of progranulin by matrix metalloproteinase-12 (MMP-12). PLoS One. 2012;7(4):e35115. https://doi.org/10.1371/journal.pone.0035115.CrossRefPubMedPubMedCentral

16.

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

17.

Stoka V, Turk V, Turk B. Lysosomal cathepsins and their regulation in aging and neurodegeneration. Ageing Res Rev. 2016;32:22–37. https://doi.org/10.1016/j.arr.2016.04.010.CrossRefPubMed

18.

Ketterer S, Gomez-Auli A, Hillebrand LE, Petrera A, Ketscher A, Reinheckel T. Inherited diseases caused by mutations in cathepsin protease genes. FEBS J. 2016;doi: https://doi.org/10.1111/febs.13980.

19.

Sevenich L, Pennacchio LA, Peters C, Reinheckel T. Human cathepsin L rescues the neurodegeneration and lethality in cathepsin B/L double-deficient mice. Biol Chem. 2006;387(7):885–91. https://doi.org/10.1515/BC.2006.112.CrossRefPubMed

20.

Lee CW, Stankowski JN, Chew J, Cook CN, Lam YW, Almeida S, et al. The lysosomal protein cathepsin L is a progranulin protease. Mol Neurodegener. 2017;12(1):55. https://doi.org/10.1186/s13024-017-0196-6.CrossRefPubMedPubMedCentral

21.

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

22.

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

23.

Vancha AR, Govindaraju S, Parsa KV, Jasti M, Gonzalez-Garcia M, Ballestero RP. Use of polyethyleneimine polymer in cell culture as attachment factor and lipofection enhancer. BMC Biotechnol. 2004;4:23. https://doi.org/10.1186/1472-6750-4-23.CrossRefPubMedPubMedCentral

24.

Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann H, et al. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J. 1995;14(15):3599–608.PubMedPubMedCentral

25.

Halangk W, Lerch MM, Brandt-Nedelev B, Roth W, Ruthenbuerger M, Reinheckel T, et al. Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J Clin Invest. 2000;106(6):773–81. https://doi.org/10.1172/JCI9411.CrossRefPubMedPubMedCentral

26.

Roth W, Deussing J, Botchkarev VA, Pauly-Evers M, Saftig P, Hafner A, et al. Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J. 2000;14(13):2075–86. https://doi.org/10.1096/fj.99-0970com 14/13/2075 14/13/2075.CrossRefPubMed

27.

Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci U S A. 1998;95(23):13453–8.CrossRefPubMedPubMedCentral

28.

Sevenich L, Schurigt U, Sachse K, Gajda M, Werner F, Muller S, et al. Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice. Proc Natl Acad Sci U S A. 2010;107(6):2497–502. https://doi.org/10.1073/pnas.0907240107.CrossRefPubMedPubMedCentral

Title: Lysosomal processing of progranulin
Authors: Xiaolai Zhou
Daniel H. Paushter
Tuancheng Feng
Lirong Sun
Thomas Reinheckel
Fenghua Hu
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Molecular Neurodegeneration / Issue 1/2017
Electronic ISSN: 1750-1326
DOI: https://doi.org/10.1186/s13024-017-0205-9

At a glance: The STEP trials

Springer Medicine

Lysosomal processing of progranulin

Abstract

Background

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Results

Conclusions

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