Intracellular Proteolysis of Progranulin Generates Stable, Lysosomal Granulins that Are Haploinsufficient in Patients with Frontotemporal Dementia Caused by GRN Mutations

Abstract

Homozygous or heterozygous mutations in the GRN gene, encoding progranulin (PGRN), cause neuronal ceroid lipofuscinosis (NCL) or frontotemporal dementia (FTD), respectively. NCL and FTD are characterized by lysosome dysfunction and neurodegeneration, indicating PGRN is important for lysosome homeostasis in the brain. PGRN is trafficked to the lysosome where its functional role is unknown. PGRN can be cleaved into seven 6-kDa proteins called granulins (GRNs); however, little is known about how GRNs are produced or if levels of GRNs are altered in FTD- GRN mutation carriers. Here, we report the identification and characterization of antibodies that reliably detect several human GRNs by immunoblot and immunocytochemistry. Using these tools, we find that endogenous GRNs are present within multiple cell lines and are constitutively produced. Further, extracellular PGRN is endocytosed and rapidly processed into stable GRNs within lysosomes. Processing of PGRN into GRNs is conserved between humans and mice and is modulated by sortilin expression and mediated by cysteine proteases (i.e. cathpesin L). Induced lysosome dysfunction caused by alkalizing agents or increased expression of transmembrane protein 106B (TMEM106B) inhibit processing of PGRN into GRNs. Finally, we find that multiple GRNs are haploinsufficient in primary fibroblasts and cortical brain tissue from FTD- GRN patients. Taken together, our findings raise the interesting possibility that GRNs carry out critical lysosomal functions and that loss of GRNs should be explored as an initiating factor in lysosomal dysfunction and neurodegeneration caused by GRN mutations.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 84

1. 1.

   Ahmed Z, Sheng H, Xu Y-f, Lin W-L, Innes AE, Gass J, Yu X, Hou H, Chiba S, Yamanouchi K, Leissring M, Petrucelli L, Nishihara M, Hutton ML, McGowan E, Dickson DW, Lewis J (2010 ) Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol 177:311–324.

   Not in our library10.2353/ajpath.2010.090915

2. 2.

   Almeida MR, Macário 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.e1–200.e5.

   Not in our library10.1016/j.neurobiolaging.2016.02.019

3. 3.

   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.

   Not in our library10.1371/journal.pone.0026454

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, et al. (2006 ) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919.

   Not in our library10.1038/nature05016

5. 5.

   Bang J, Spina S, Miller BL (2015 ) Frontotemporal dementia. Lancet 386:1672–1682.

   Not in our library10.1016/s0140-6736(15)00461-4

6. 6.

   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.

   Not in our library10.1016/s0006-291x(05)80908-8

7. 7.

   Belcourt DR, Lazure C, Bennett HP (1993 ) Isolation and primary structure of the three major forms of granulin-like peptides from hematopoietic tissues of a teleost fish (Cyprinus carpio). J Biol Chem 268:9230–9237.

   Not in our library

8. 8.

   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.

   Not in our library10.1093/hmg/dds475

9. 9.

   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.

   Not in our library10.1093/hmg/ddw127

10. 10.

    Canafoglia L, Morbin M, Scaioli V, Pareyson D, D'Incerti L, Fugnanesi V, Tagliavini F, Berkovic SF, Franceschetti S (2014 ) Recurrent generalized seizures, visual loss, and palinopsia as phenotypic features of neuronal ceroid lipofuscinosis due to progranulin gene mutation. Epilepsia 55:e56–e59.

    Not in our library10.1111/epi.12632

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 31:1885–1894.

    Not in our library10.1523/jneurosci.5757-10.2011

12. 12.

    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.

    Not in our library10.1016/j.ajhg.2010.11.002

13. 13.

    Carvelli L, Libin Y, Morales CR (2015 ) Prosaposin: a protein with differential sorting and multiple functions. Histol Histopathol 30:647–660.

    Not in our library10.14670/hh-30.647

14. 14.
    Capsid Serotype and Timing of Injection Determines AAV Transduction in the Neonatal Mice Brain · 2013

    No notice
15. 15.

    Chang KH, Chen CM, Chen YC, Hsiao YC, Huang CC, Kuo HC, Hsu HC, Lee-Chen GJ, Wu YR (2013 ) Association between GRN rs5848 polymorphism and Parkinson's disease in Taiwanese population. PLoS One 8:e54448.

    Not in our library10.1371/journal.pone.0054448

16. 16.

    Chen-Plotkin AS, Xiao J, Geser F, Martinez-Lage M, Grossman M, Unger T, Wood EM, Van Deerlin VM, Trojanowski JQ, Lee VM (2010 ) Brain progranulin expression in GRN-associated frontotemporal lobar degeneration. Acta Neuropathol 119:111–122.

    Not in our library10.1007/s00401-009-0576-2

17. 17.

    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.

    Not in our library10.1523/jneurosci.0521-12.2012

18. 18.

    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.

    Not in our library10.1523/jneurosci.5336-12.2013

19. 19.

    Chen Y, Li S, Su L, Sheng J, Lv W, Chen G, Xu Z (2015 ) Association of progranulin polymorphism rs5848 with neurodegenerative diseases: a meta-analysis. J Neurol 262:814–822.

    Not in our library10.1007/s00415-014-7630-2

20. 20.

    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, et al. (2006 ) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924.

    Not in our library10.1038/nature05017

21. 21.

    Essletzbichler P, Konopka T, Santoro F, Chen D, Gapp BV, Kralovics R, Brummelkamp TR, Nijman SM, Bürckstümmer T (2014 ) Megabase-scale deletion using CRISPR/Cas9 to generate a fully haploid human cell line. Genome Res 24:2059–2065.

    Not in our library10.1101/gr.177220.114

22. 22.

    Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, Bisceglio G, Rovelet-Lecrux A, Boeve B, Petersen RC, Dickson DW, Younkin SG, Deramecourt V, Crook J, Graff-Radford NR, Rademakers R (2009 ) Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain 132:583–591.

    Not in our library10.1093/brain/awn352

23. 23.

    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, et al. (2011 ) TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 76:467–474.

    Not in our library10.1212/wnl.0b013e31820a0e3b

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, et al. (2006 ) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15:2988–3001.

    Not in our library10.1093/hmg/ddl241

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 71:1235–1239.

    Not in our library10.1212/01.wnl.0000325058.10218.fc

26. 26.

    Ghidoni R, Paterlini A, Albertini V, Binetti G, Benussi L (2012a ) Losing protein in the brain: the case of progranulin. Brain Res 1476:172–182.

    Not in our library10.1016/j.brainres.2012.01.075

27. 27.

    Ghidoni R, Stoppani E, Rossi G, Piccoli E, Albertini V, Paterlini A, Glionna M, Pegoiani E, Agnati LF, Fenoglio C, Scarpini E, Galimberti D, Morbin M, Tagliavini F, Binetti G, Benussi L (2012b ) Optimal plasma progranulin cutoff value for predicting null progranulin mutations in neurodegenerative diseases: a multicenter Italian study. Neurodegener Dis 9:121–127.

    Not in our library10.1159/000333132

28. 28.

    Götzl 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.

    Not in our library10.1007/s00401-014-1262-6

29. 29.

    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.

    Not in our library10.1073/pnas.1510329112

30. 30.

    Holler CJ, Taylor G, McEachin ZT, Deng Q, Watkins WJ, Hudson K, Easley CA, Hu WT, Hales CM, Rossoll W, Bassell GJ, Kukar T (2016 ) Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia. Mol Neurodegener 11:46.

    Not in our library10.1186/s13024-016-0114-3

31. 31.

    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.

    Not in our library10.1038/nsb0996-747

32. 32.

    Hu F, Padukkavidana T, Vægter 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.

    Not in our library10.1016/j.neuron.2010.09.034

33. 33.

    Kelley BJ, Haidar W, Boeve BF, Baker M, Shiung M, Knopman DS, Rademakers R, Hutton M, Adamson J, Kuntz KM, Dickson DW, Parisi JE, Smith GE, Petersen RC (2010 ) Alzheimer disease-like phenotype associated with the c.154delA mutation in progranulin. Arch Neurol 67:171–177.

    Not in our library10.1001/archneurol.2010.113

34. 34.

    Kessenbrock K, Fröhlich L, Sixt M, Lämmermann T, Pfister H, Bateman A, Belaaouaj A, Ring J, Ollert M, Fässler R, Jenne DE (2008 ) Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest 118:2438–2447.

    Not in our library10.1172/jci34694

35. 35.

    Kleinberger G, Capell A, Haass C, Van Broeckhoven C (2013 ) Mechanisms of granulin deficiency: lessons from cellular and animal models. Mol Neurobiol 47:337–360.

    Not in our library10.1007/s12035-012-8380-8

36. 36.

    Kleinberger G, Wils H, Ponsaerts P, Joris G, Timmermans J-P, Van Broeckhoven C, Kumar-Singh S (2010 ) Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J Neurochem 115:735–747.

    Not in our library10.1111/j.1471-4159.2010.06961.x

37. 37.

    Kollmann K, Mutenda KE, Balleininger M, Eckermann E, von Figura K, Schmidt B, Lübke T (2005 ) Identification of novel lysosomal matrix proteins by proteome analysis. Proteomics 5:3966–3978.

    Not in our library10.1002/pmic.200401247

38. 38.

    Kuchar L, Ledvinová J, Hrebícek M, Mysková H, Dvoráková L, Berná L, Chrastina P, Asfaw B, Elleder M, Petermöller M, Mayrhofer H, Staudt M, Krägeloh-Mann I, Paton BC, Harzer K (2009 ) Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am J Med Genet A 149A:613–621.

    Not in our library10.1002/ajmg.a.32712

39. 39.

    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.

    Not in our library10.1159/000322538

40. 40.

    Lefrancois S, Zeng J, Hassan AJ, Canuel M, Morales CR (2003 ) The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin. EMBO J 22:6430–6437.

    Not in our library10.1093/emboj/cdg629

Cited by papers we hold 1

• Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons · 2020
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.