Tissue plasminogen activator in brain tissues infected with transmissible spongiform encephalopathies.
Prion propagation involves conversion of host PrP(C) to a disease-related isoform, PrP(Sc), which accumulates during disease and is the principal component of the transmissible agent. Proteolysis seems to play an important role in PrP metabolism. Plasminogen, a serine protease precursor, has been shown to interact with PrP(Sc). Plasminogen can be proteolytically activated by tissue plasminogen activator (tPA). Recent reports imply a crosstalk between tPA-mediated plasmin activation and PrP. In our study, both tPA activity and tPA gene expression were found elevated in TSE-infected brains as compared to their normal counterparts. Furthermore, it was proved that PrP(Sc), in contrast to PrP(C), could not be degraded by plasmin. In addition, it was observed that TSE symptoms and subsequent death of plasminogen-deficient and tPA-deficient scrapie challenged mice preceded that of wild-type controls. Our data imply that enhanced tPA activity observed in prion infected brains may reflect a neuro-protective response.
Xanthopoulos
K
K
Prion Disease Research Group, Laboratory of Pharmacology, Department of Pharmaceutical Sciences, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Paspaltsis
I
I
Apostolidou
V
V
Petrakis
S
S
Siao
C J
CJ
Kalpatsanidis
A
A
Grigoriadis
N
N
Tsaftaris
A
A
Tsirka
S E
SE
Sklaviadis
T
T
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D006224:Cricetinae; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D018621:PrPC Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism* / Q000503:physiopathology; D012608:Scrapie / Q000378:metabolism / Q000503:physiopathology; D012756:Sheep; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D018621:PrPC Proteins; D018620:PrPSc Proteins; D010447:Peptide Hydrolases; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin