title: Unfolded protein response in Gaucher disease: from human to Drosophila.
abstract: BACKGROUND
  In Gaucher disease (GD), resulting from mutations in the GBA gene, mutant β-glucocerebrosidase (GCase) molecules are recognized as misfolded in the endoplasmic reticulum (ER). They are retrotranslocated to the cytoplasm, where they are ubiquitinated and undergo proteasomal degradation in a process known as the ER Associated Degradation (ERAD). We have shown in the past that the degree of ERAD of mutant GCase correlates with GD severity.Persistent presence of mutant, misfolded protein molecules in the ER leads to ER stress and evokes the unfolded protein response (UPR).
  
  
  METHODS
  We investigated the presence of UPR in several GD models, using molecular and behavioral assays.
  
  
  RESULTS
  Our results show the existence of UPR in skin fibroblasts from GD patients and carriers of GD mutations. We could recapitulate UPR in two different Drosophila models for carriers of GD mutations: flies heterozygous for the endogenous mutant GBA orthologs and flies expressing the human N370S or L444P mutant GCase variants. We encountered early death in both fly models, indicating the deleterious effect of mutant GCase during development. The double heterozygous flies, and the transgenic flies, expressing mutant GCase in dopaminergic/serotonergic cells developed locomotion deficit.
  
  
  CONCLUSIONS
  Our results strongly suggest that mutant GCase induces the UPR in GD patients as well as in carriers of GD mutations and leads to development of locomotion deficit in flies heterozygous for GD mutations.
authors.affiliation: Department of Cell Research and Immunology, Tel Aviv University, Levanon St, Ramat Aviv 69978, Israel. horwitzm@post.tau.ac.il.
authors.forename: Gali
authors.initials: G
authors.lastname: Maor
authors.forename: Sigal
authors.initials: S
authors.lastname: Rencus-Lazar
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.forename: Hermann
authors.initials: H
authors.lastname: Steller
authors.forename: Daniel
authors.initials: D
authors.lastname: Segal
authors.forename: Mia
authors.initials: M
authors.lastname: Horowitz
mesh_terms: D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005776:Gaucher Disease / Q000378:metabolism* / Q000473:pathology; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*
chemical_list: D005962:Glucosylceramidase
references.citation: J Biochem. 1994 Jan;115(1):113-9
references.pmid: 8188616
references.citation: Hum Mol Genet. 2008 Feb 15;17(4):469-77
references.pmid: 17989065
references.citation: Acta Neuropathol. 2011 Aug;122(2):187-204
references.pmid: 21720849
references.citation: Neurosci Lett. 2006 Aug 14;404(1-2):163-5
references.pmid: 16781064
references.citation: Intern Med. 2006;45(20):1165-7
references.pmid: 17106163
references.citation: Mol Genet Metab. 2011 Apr;102(4):436-47
references.pmid: 21257328
references.citation: Mov Disord. 2005 Jan;20(1):100-3
references.pmid: 15517591
references.citation: Arch Neurol. 2009 May;66(5):578-83
references.pmid: 19433657
references.citation: Am J Physiol Cell Physiol. 2006 Apr;290(4):C1076-82
references.pmid: 16531566
references.citation: Synapse. 2011 Dec;65(12):1289-97
references.pmid: 21633975
references.citation: Cell. 2008 Jan 11;132(1):24-6
references.pmid: 18191217
references.citation: Hum Mutat. 2008 May;29(5):567-83
references.pmid: 18338393
references.citation: Mol Biotechnol. 2006 Oct;34(2):279-90
references.pmid: 17172673
references.citation: Cell Death Dis. 2011 Apr 28;2:e149
references.pmid: 21525936
references.citation: Blood Cells Mol Dis. 2011 Jan 15;46(1):4-10
references.pmid: 21106416
references.citation: Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10544-7
references.pmid: 1961718
references.citation: Neurodegener Dis. 2012;10(1-4):195-202
references.pmid: 22327140
references.citation: Hum Mol Genet. 2005 Aug 15;14(16):2387-98
references.pmid: 16000318
references.citation: Neurology. 2009 Oct 27;73(17):1424-5, author reply 1425-6
references.pmid: 19858467
references.citation: Br J Haematol. 2005 Apr;129(2):178-88
references.pmid: 15813845
references.citation: Prog Mol Biol Transl Sci. 2012;107:189-214
references.pmid: 22482451
references.citation: Neurology. 2006 Sep 12;67(5):908-10
references.pmid: 16790605
references.citation: Cell Stress Chaperones. 2012 Mar;17(2):275-9
references.pmid: 22038282
references.citation: Am J Med Genet A. 2003 Feb 1;116A(4):348-51
references.pmid: 12522789
references.citation: Hum Mol Genet. 2009 Apr 15;18(8):1482-8
references.pmid: 19193629
references.citation: Hum Mol Genet. 2011 Jan 1;20(1):202-10
references.pmid: 20947659
references.citation: Hum Mol Genet. 2010 Oct 1;19(19):3771-81
references.pmid: 20643691
references.citation: N Engl J Med. 2005 Feb 17;352(7):728-31; author reply 728-31
references.pmid: 15716572
references.citation: Cell. 2011 Jul 8;146(1):37-52
references.pmid: 21700325
references.citation: Cell Mol Life Sci. 2012 Aug;69(15):2465-8
references.pmid: 22678664
references.citation: Neurodegener Dis. 2011;8(3):124-8
references.pmid: 20714112
references.citation: N Engl J Med. 2009 Oct 22;361(17):1651-61
references.pmid: 19846850
references.citation: Cell. 2011 Mar 4;144(5):689-702
references.pmid: 21376232
references.citation: Curr Biol. 2012 Aug 21;22(16):R622-6
references.pmid: 22917505
references.citation: Mol Genet Metab. 2004 Jan;81(1):70-3
references.pmid: 14728994
references.citation: J Biol Chem. 1985 Nov 15;260(26):14319-24
references.pmid: 3932353
references.citation: Nat Cell Biol. 2000 Dec;2(12):915-21
references.pmid: 11146656
references.citation: Cell. 2008 Sep 5;134(5):769-81
references.pmid: 18775310
references.citation: Mol Genet Metab. 2003 Jun;79(2):104-9
references.pmid: 12809640
references.citation: Mol Genet Metab. 2008 Apr;93(4):426-36
references.pmid: 18160322
references.citation: N Engl J Med. 1987 Mar 5;316(10):570-5
references.pmid: 2880291
references.citation: Neurology. 2007 Sep 18;69(12):1270-7
references.pmid: 17875915
references.citation: Biochem Biophys Res Commun. 2011 Sep 23;413(2):254-8
references.pmid: 21884680
references.citation: Mol Genet Metab. 2001 Aug;73(4):313-21
references.pmid: 11509013
references.citation: Med Sci (Paris). 2007 Mar;23(3):291-6
references.pmid: 17349291
references.citation: J Med Genet. 2004 Dec;41(12):937-40
references.pmid: 15591280
references.citation: Neurology. 2003 Jul 8;61(1):99-101
references.pmid: 12847165
references.citation: Ann Neurol. 2011 Jun;69(6):940-53
references.pmid: 21472771
references.citation: Diabetes Obes Metab. 2010 Oct;12 Suppl 2:99-107
references.pmid: 21029306
references.citation: N Engl J Med. 2004 Nov 4;351(19):1972-7
references.pmid: 15525722
references.citation: Proc Natl Acad Sci U S A. 1988 Apr;85(7):2349-52
references.pmid: 3353383
references.citation: N Engl J Med. 2005 Feb 17;352(7):728-31; author reply 728-31
references.pmid: 15719451
references.citation: J Neurol Neurosurg Psychiatry. 2006 May;77(5):709-10
references.pmid: 16614047
references.citation: Neuroscience. 2013 Mar 1;232:90-105
references.pmid: 23262240
references.citation: Cell Cycle. 2008 Apr 1;7(7):865-9
references.pmid: 18414035
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12101-6
references.pmid: 21730160
references.citation: Neurology. 2011 Jan 18;76(3):301-3
references.pmid: 21242499
references.citation: Science. 2011 Nov 25;334(6059):1081-6
references.pmid: 22116877
references.citation: Mol Genet Metab. 2005 Apr;84(4):302-4
references.pmid: 15781189
references.citation: J Cell Biol. 2012 Jun 25;197(7):857-67
references.pmid: 22733998
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3537-42
references.pmid: 23297226
references.citation: Proc Jpn Acad Ser B Phys Biol Sci. 2012;88(1):18-30
references.pmid: 22241068
references.citation: N Engl J Med. 2005 Feb 17;352(7):728-31; author reply 728-31
references.pmid: 15719452
references.citation: Hum Mutat. 1996;8(3):207-13
references.pmid: 8889578
references.citation: Int Rev Cell Mol Biol. 2011;292:197-280
references.pmid: 22078962
references.citation: Arch Neurol. 2009 May;66(5):571-6
references.pmid: 19433656
references.citation: PLoS One. 2012;7(7):e38837
references.pmid: 22792159
references.citation: Mov Disord. 2005 Mar;20(3):367-70
references.pmid: 15517592
references.citation: Arch Neurol. 2007 Jul;64(7):1056-8
references.pmid: 17620502
references.citation: Arch Neurol. 2008 Oct;65(10):1353-7
references.pmid: 18852351
references.citation: Blood Cells Mol Dis. 2005 Jul-Aug;35(1):57-65
references.pmid: 15916907
references.citation: Hum Mutat. 2012 Oct;33(10):1398-407
references.pmid: 22623374
references.citation: Cell. 2005 Dec 16;123(6):1079-92
references.pmid: 16360037
references.citation: Nature. 2000 Mar 23;404(6776):394-8
references.pmid: 10746727