title: Lack of a-disintegrin-and-metalloproteinase ADAM10 leads to intracellular accumulation and loss of shedding of the cellular prion protein in vivo.
abstract: BACKGROUND
  The cellular prion protein (PrPC) fulfils several yet not completely understood physiological functions. Apart from these functions, it has the ability to misfold into a pathogenic scrapie form (PrPSc) leading to fatal transmissible spongiform encephalopathies. Proteolytic processing of PrPC generates N- and C-terminal fragments which play crucial roles both in the pathophysiology of prion diseases and in transducing physiological functions of PrPC. A-disintegrin-and-metalloproteinase 10 (ADAM10) has been proposed by cell culture experiments to be responsible for both shedding of PrPC and its α-cleavage. Here, we analyzed the role of ADAM10 in the proteolytic processing of PrPC in vivo.
  
  
  RESULTS
  Using neuron-specific Adam10 knockout mice, we show that ADAM10 is the sheddase of PrPC and that its absence in vivo leads to increased amounts and accumulation of PrPC in the early secretory pathway by affecting its posttranslational processing. Elevated PrPC levels do not induce apoptotic signalling via p53. Furthermore, we show that ADAM10 is not responsible for the α-cleavage of PrPC.
  
  
  CONCLUSIONS
  Our study elucidates the proteolytic processing of PrPC and proves a role of ADAM10 in shedding of PrPC in vivo. We suggest that ADAM10 is a mediator of PrPC homeostasis at the plasma membrane and, thus, might be a regulator of the multiple functions discussed for PrPC. Furthermore, identification of ADAM10 as the sheddase of PrPC opens the avenue to devising novel approaches for therapeutic interventions against prion diseases.
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany. m.glatzel@uke.de.
authors: Hermann C
authors: HC
authors: Altmeppen
authors: Johannes
authors: J
authors: Prox
authors: Berta
authors: B
authors: Puig
authors: Mark A
authors: MA
authors: Kluth
authors: Christian
authors: C
authors: Bernreuther
authors: Dana
authors: D
authors: Thurm
authors: Ellen
authors: E
authors: Jorissen
authors: Bettina
authors: B
authors: Petrowitz
authors: Udo
authors: U
authors: Bartsch
authors: Bart
authors: B
authors: De Strooper
authors: Paul
authors: P
authors: Saftig
authors: Markus
authors: M
authors: Glatzel
references: J Neurobiol. 2006 Oct;66(12):1378-95
references: 16967505
references: Brain. 2010 Nov;133(11):3323-35
references: 20805102
references: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3922-7
references: 10097139
references: FASEB J. 2006 Feb;20(2):317-9
references: 16352647
references: Neuroscience. 2010 Sep 15;169(4):1640-50
references: 20547212
references: Genes Dev. 2002 Jan 15;16(2):209-21
references: 11799064
references: J Invest Dermatol. 2009 Jun;129(6):1471-82
references: 18971959
references: J Biol Chem. 2005 Oct 28;280(43):35914-21
references: 16120605
references: PLoS One. 2010 Feb 08;5(2):e9107
references: 20161712
references: Biochem Soc Trans. 2005 Apr;33(Pt 2):335-8
references: 15787600
references: Neurobiol Dis. 2009 Nov;36(2):233-41
references: 19632330
references: FEBS Lett. 2005 Nov 21;579(28):6333-7
references: 16263114
references: J Biol Chem. 2005 Dec 9;280(49):40624-31
references: 16236709
references: Science. 2000 Aug 25;289(5483):1360-5
references: 10958785
references: J Neurosci. 2005 May 11;25(19):4879-88
references: 15888663
references: EMBO J. 2010 Sep 1;29(17):3020-32
references: 20676056
references: Glia. 2000 May;30(3):301-10
references: 10756079
references: J Cell Biol. 1999 Oct 18;147(2):277-94
references: 10525535
references: Nat Neurosci. 2010 Mar;13(3):310-8
references: 20098419
references: Nat Rev Mol Cell Biol. 2001 Feb;2(2):118-26
references: 11252953
references: J Neurosci. 2009 May 20;29(20):6752-60
references: 19458243
references: Mol Cell Neurosci. 2009 Feb;40(2):242-8
references: 19056496
references: J Biol Chem. 2009 Aug 21;284(34):22590-600
references: 19564338
references: Nature. 1992 Apr 16;356(6370):577-82
references: 1373228
references: J Biol Chem. 2009 Dec 18;284(51):35973-86
references: 19850936
references: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3416-21
references: 16492732
references: J Biol Chem. 2001 Jan 19;276(3):2286-91
references: 11060296
references: J Biol Chem. 2001 Oct 12;276(41):37743-6
references: 11477090
references: BMC Genomics. 2009 Apr 28;10:201
references: 19400950
references: EMBO J. 2005 Feb 23;24(4):742-52
references: 15692570
references: PLoS Pathog. 2010 Mar 05;6(3):e1000800
references: 20221436
references: J Biol Chem. 2007 Jan 19;282(3):1956-63
references: 17121821
references: Hum Mol Genet. 2002 Oct 1;11(21):2615-24
references: 12354787
references: Nat Genet. 1999 Sep;23(1):99-103
references: 10471508
references: J Neurosci. 2010 Apr 7;30(14):4833-44
references: 20371803
references: Cell. 2005 Oct 21;123(2):291-304
references: 16239146
references: J Biol Chem. 2004 Mar 19;279(12):11170-8
references: 14711812
references: Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11062-7
references: 17573534
references: EMBO J. 1996 Mar 15;15(6):1255-64
references: 8635458
references: J Biol Chem. 2004 Jan 2;279(1):612-8
references: 14570892
references: PLoS Biol. 2005 Sep;3(9):e283
references: 16086633
references: Cell. 1997 Jul 25;90(2):271-80
references: 9244301
references: EMBO J. 2007 Jun 6;26(11):2777-85
references: 17510630
references: Nature. 2009 Feb 26;457(7233):1128-32
references: 19242475
references: Neuron. 2001 Jul 19;31(1):25-34
references: 11498048
references: Brain Res Mol Brain Res. 2005 Aug 18;138(2):182-90
references: 15908040
references: Development. 1997 Dec;124(23):4759-67
references: 9428412
references: J Biol Chem. 1995 Aug 11;270(32):19173-80
references: 7642585
references: Science. 1982 Apr 9;216(4542):136-44
references: 6801762
references: J Biol Chem. 2003 Mar 21;278(12):10061-6
references: 12529324
references: Nat Rev Cancer. 2008 Dec;8(12):929-41
references: 19005493
references: Nat Rev Cancer. 2009 Oct;9(10):724-37
references: 19776742
references: Cell. 1998 Apr 17;93(2):203-14
references: 9568713
references: J Virol. 2011 Feb;85(4):1484-94
references: 21123371
references: Am J Pathol. 1998 Nov;153(5):1561-72
references: 9811348