Crucial role for prion protein membrane anchoring in the neuroinvasion and neural spread of prion infection.
In nature prion diseases are usually transmitted by extracerebral prion infection, but clinical disease results only after invasion of the central nervous system (CNS). Prion protein (PrP), a host-encoded glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein, is necessary for prion infection and disease. Here, we investigated the role of the anchoring of PrP on prion neuroinvasion by studying various inoculation routes in mice expressing either anchored or anchorless PrP. In control mice with anchored PrP, intracerebral or sciatic nerve inoculation resulted in rapid CNS neuroinvasion and clinical disease (154 to 156 days), and after tongue, ocular, intravenous, or intraperitoneal inoculation, CNS neuroinvasion was only slightly slower (193 to 231 days). In contrast, in anchorless PrP mice, these routes resulted in slow and infrequent CNS neuroinvasion. Only intracerebral inoculation caused brain PrPres, a protease-resistant isoform of PrP, and disease in both types of mice. Thus, anchored PrP was an essential component for the rapid neural spread and CNS neuroinvasion of prion infection.
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA.
Mikael
M
Klingeborn
Brent
B
Race
Kimberly D
KD
Meade-White
Rebecca
R
Rosenke
James F
JF
Striebel
Bruce
B
Chesebro
D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism / Q000503:physiopathology; D011328:Prions / Q000378:metabolism* / Q000472:pathogenicity*; D012584:Sciatic Nerve / Q000378:metabolism; D012608:Scrapie / Q000378:metabolism / Q000503:physiopathology*; D013116:Spinal Cord / Q000378:metabolism; D014059:Tongue / Q000378:metabolism
D018620:PrPSc Proteins; D011328:Prions