Prion protein with an insertional mutation accumulates on axonal and dendritic plasmalemma and is associated with distinctive ultrastructural changes.
Prion diseases are fatal neurological diseases characterized by central nervous system deposition of abnormal forms of a membrane glycoprotein designated PrP (prion protein). Tg(PG14) transgenic mice express PrP that harbor a nine-octapeptide insertional mutation homologous to one described in a familial prion disease of humans. Tg(PG14) mice spontaneously develop a fatal neurological illness accompanied by massive apoptosis of cerebellar granule neurons and accumulation of an aggregated and weakly protease-resistant form of PrP that is not infectious. Previous light microscopic analyses of these mice left open questions regarding the subcellular distribution of the mutant protein and the nature of the neuropathological lesions produced. To address these questions, we undertook an immunogold electron microscopic study of Tg(PG14) mice. We found that mutant PrP is localized primarily on the plasma membrane of dendrites and unmyelinated axons in the hippocampus and cerebellum, with little labeling of either neuronal cell bodies or intracellular organelles. PrP deposits were shown to be associated with degenerative changes in dendritic structure. We also describe for the first time marked pathology in myelinated axons, and alterations in the axon/oligodendrocyte interface. Taken together, our results suggest cellular mechanisms by which mutant PrPs produce pathology. In addition, they highlight distinctions between familial and infectious prion disorders at the ultrastructural level that correlate with differences in cellular trafficking of the disease-associated PrP forms.
Jeffrey
Martin
M
Veterinary Laboratories Agency, Lasswade Laboratory, Pentlands Science Park, Bush Loan, Penicuik, Midlothian, Scotland. m.jeffrey@vla.defra.gsi.gov.uk
Goodsir
Caroline
C
McGovern
Gillian
G
Barmada
Sami J
SJ
Medrano
Andrea Z
AZ
Harris
David A
DA
D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002531:Cerebellum / Q000378:metabolism* / Q000648:ultrastructure; D003712:Dendrites / Q000378:metabolism* / Q000648:ultrastructure; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism / Q000648:ultrastructure; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011328:Prions / Q000235:genetics* / Q000378:metabolism
D011328:Prions
Brain Res. 1994 Sep 12;656(2):329-43
7820594
Neuropathol Appl Neurobiol. 2000 Feb;26(1):41-54
10736066
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9683-8
15210972
J Comp Pathol. 2005 May;132(4):273-82
15893985
J Biol Chem. 1992 Aug 15;267(23):16188-99
1353761
J Neurosci. 2003 Aug 6;23(18):7183-93
12904479
Eur J Neurosci. 2002 Apr;15(7):1163-77
11982627
J Biol Chem. 2001 Nov 9;276(45):42409-21
11527974
Neurobiol Dis. 2008 Jul;31(1):20-32
18514536
Acta Neurobiol Exp (Wars). 1999 Sep 30;59(3):177-180
38087506
J Virol. 2003 Jul;77(13):7611-22
12805461
J Virol. 1991 Dec;65(12):6597-603
1682507
Annu Rev Pathol. 2008;3:11-40
18233951
Toxicol Appl Pharmacol. 1971 Apr;18(4):869-82
5570239
Mol Cell Neurosci. 2005 Nov;30(3):304-15
16139509
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5574-9
10805813
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
9811807
Neuron. 1998 Dec;21(6):1339-51
9883727
Br Med Bull. 2003;66:71-85
14522850
Nature. 1997 Nov 6;390(6655):74-7
9363892
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4712-7
17360589
Neurobiol Dis. 2004 Aug;16(3):527-37
15262264
Ann Neurol. 2004 Jun;55(6):781-92
15174012
Neuropathol Appl Neurobiol. 1997 Apr;23(2):93-101
9160894
J Biol Chem. 2003 Jun 13;278(24):21732-43
12663673
Neurobiol Dis. 2001 Oct;8(5):743-63
11592845
Neuropathol Appl Neurobiol. 2009 Jun;35(3):259-71
19473293
J Biol Chem. 1997 Apr 25;272(17):11604-12
9111077
J Biol Chem. 2005 Mar 25;280(12):11320-8
15632159
J Biol Chem. 1991 Sep 25;266(27):18217-23
1680859
J Virol. 1991 Jul;65(7):3667-75
1710287
Brain Pathol. 2009 Jan;19(1):1-11
18400047
J Virol Methods. 1989 Apr-May;24(1-2):215-21
2569471
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):238-43
15618403
J Neurochem. 2008 Mar;104(5):1293-308
18034781