title: A mutant prion protein sensitizes neurons to glutamate-induced excitotoxicity.
abstract: Growing evidence suggests that a physiological activity of the cellular prion protein (PrP(C)) plays a crucial role in several neurodegenerative disorders, including prion and Alzheimer's diseases. However, how the functional activity of PrP(C) is subverted to deliver neurotoxic signals remains uncertain. Transgenic (Tg) mice expressing PrP with a deletion of residues 105-125 in the central region (referred to as ΔCR PrP) provide important insights into this problem. Tg(ΔCR) mice exhibit neonatal lethality and massive degeneration of cerebellar granule neurons, a phenotype that is dose dependently suppressed by the presence of wild-type PrP. When expressed in cultured cells, ΔCR PrP induces large, ionic currents that can be detected by patch-clamping techniques. Here, we tested the hypothesis that abnormal ion channel activity underlies the neuronal death seen in Tg(ΔCR) mice. We find that ΔCR PrP induces abnormal ionic currents in neurons in culture and in cerebellar slices and that this activity sensitizes the neurons to glutamate-induced, calcium-mediated death. In combination with ultrastructural and biochemical analyses, these results demonstrate a role for glutamate-induced excitotoxicity in PrP-mediated neurodegeneration. A similar mechanism may operate in other neurodegenerative disorders attributable to toxic, β-rich oligomers that bind to PrP(C).
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA. biasini@bu.edu, daharris@bu.edu
authors: Emiliano
authors: E
authors: Biasini
authors: Ursula
authors: U
authors: Unterberger
authors: Isaac H
authors: IH
authors: Solomon
authors: Tania
authors: T
authors: Massignan
authors: Assunta
authors: A
authors: Senatore
authors: Hejiao
authors: H
authors: Bian
authors: Till
authors: T
authors: Voigtlaender
authors: Frederick P
authors: FP
authors: Bowman
authors: Valentina
authors: V
authors: Bonetto
authors: Roberto
authors: R
authors: Chiesa
authors: Jennifer
authors: J
authors: Luebke
authors: Paul
authors: P
authors: Toselli
authors: David A
authors: DA
authors: Harris
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018698:Glutamic Acid / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL / Q000502:physiology*; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018621:PrPC Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018690:Excitatory Amino Acid Agonists; D018621:PrPC Proteins; D018698:Glutamic Acid
references: J Neurochem. 2009 Jan;108(1):44-56
references: 19046329
references: Nature. 1996 Jan 25;379(6563):339-43
references: 8552188
references: J Cell Biol. 2008 May 5;181(3):551-65
references: 18443219
references: Eur J Neurosci. 2008 Feb;27(3):612-20
references: 18279314
references: PLoS One. 2012;7(3):e33472
references: 22428057
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):552-61
references: 17585315
references: Future Med Chem. 2012 Sep;4(13):1655-8
references: 22924502
references: J Neurosci. 2007 Jan 24;27(4):852-9
references: 17251426
references: J Neurosci Res. 2007 Sep;85(12):2741-55
references: 17304577
references: Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10238-43
references: 18632556
references: J Pharmacol Toxicol Methods. 2005 May-Jun;51(3):187-200
references: 15862464
references: J Biol Chem. 2010 Mar 5;285(10):7752-65
references: 19940127
references: Trends Neurosci. 2012 Feb;35(2):92-103
references: 22137337
references: Science. 2003 Oct 31;302(5646):871-4
references: 14593181
references: EMBO J. 2011 May 18;30(10):2057-70
references: 21441896
references: Neuron. 2007 Feb 1;53(3):325-35
references: 17270731
references: Neurobiol Dis. 2003 Dec;14(3):303-17
references: 14678748
references: J Physiol. 2012 Mar 15;590(6):1357-68
references: 22310309
references: J Mol Med (Berl). 2010 Apr;88(4):331-8
references: 19960174
references: EMBO J. 2007 Jan 24;26(2):548-58
references: 17245437
references: Nature. 2006 Oct 19;443(7113):803-10
references: 17051207
references: Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1737-42
references: 22307640
references: Neuron. 2006 May 4;50(3):353-7
references: 16675391
references: Prog Neurobiol. 1998 Mar;54(4):369-415
references: 9522394
references: Nature. 1992 Apr 16;356(6370):577-82
references: 1373228
references: Science. 2005 Jun 3;308(5727):1435-9
references: 15933194
references: J Biol Chem. 2011 Apr 22;286(16):14724-36
references: 21385869
references: Prion. 2009 Oct-Dec;3(4):195-201
references: 19887910
references: J Gen Physiol. 1996 Jun;107(6):695-714
references: 8783071
references: J Neurochem. 1997 Jan;68(1):319-27
references: 8978741
references: J Biol Chem. 2010 Aug 20;285(34):26719-26
references: 20573963
references: J Biol Chem. 2010 Aug 20;285(34):26377-83
references: 20576610
references: EMBO J. 1996 Mar 15;15(6):1255-64
references: 8635458
references: Nature. 2009 Feb 26;457(7233):1128-32
references: 19242475
references: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300
references: 20133875
references: Curr Issues Mol Biol. 2010;12(2):51-61
references: 19767650
references: Am J Pathol. 2010 Jun;176(6):2695-706
references: 20472884
references: Prion. 2012 Jan-Mar;6(1):40-5
references: 22453177
references: Physiol Rev. 2008 Apr;88(2):673-728
references: 18391177
references: J Biol Chem. 2010 Nov 19;285(47):36542-50
references: 20837487
references: Neuroepidemiology. 2007;28(2):118-9
references: 17409774