Increased proportions of C1 truncated prion protein protect against cellular M1000 prion infection.
Prion disease pathogenesis is linked to the cell-associated propagation of misfolded protease-resistant conformers (PrP) of the normal cellular prion protein (PrP). Ongoing PrP expression is the only known absolute requirement for successful prion disease transmission and PrP propagation. Further typifying prion disease is selective neuronal dysfunction and loss, although the precise mechanisms underlying this are undefined. We utilized a single prion strain (M1000) and a range of neuronal and nonneuronal, PrP endogenously expressing and transgenically modified overexpressing cell lines, to evaluate whether PrP glycosylation patterns or constitutive N-terminal cleavage events may be determinants of sustained PrP propagation. Our data demonstrates that relative proportions of full-length and C1 truncated PrP are the most important characteristics influencing susceptibility to sustained M1000 prion infection, supporting PrP alpha-cleavage as a protective event, which may contribute to the selective neuronal vulnerability observed in vivo.
Lewis
Victoria
V
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
Hill
Andrew F
AF
Haigh
Cathryn L
CL
Klug
Genevieve M
GM
Masters
Colin L
CL
Lawson
Victoria A
VA
Collins
Steven J
SJ
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D006031:Glycosylation; D047468:Immunoprecipitation; D016015:Logistic Models; D051379:Mice; D041681:NIH 3T3 Cells; D009474:Neurons / Q000378:metabolism; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000378:metabolism* / Q000472:pathogenicity*; D011817:Rabbits
D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions