Transmissible spongiform encephalopathies are characterized by the accumulation of PrPSc, a protease-resistant form of a host-derived protein termed PrPC. Substantial evidence indicates that PrPSc represents an essential component of the infectious agent, which is termed prion. The accumulation of PrPSc within the central nervous system of prion-infected organisms is a dynamic process that is regulated both by production and by clearance of PrPSc. Although several proteases have been implicated in proteolysis of PrPC, the mechanisms underlying proteolysis of PrPSc remain unclear. Here, it was investigated whether neprilysin, a metalloprotease known to degrade extracellular amyloidogenic proteins such as amyloid-β, plays a role in prion pathogenesis in vivo. As neprilysin has a broad substrate specificity and is localized subcellularly in the vicinity of PrP, it represents a plausible candidate for prion degradation. Prions were therefore administered to mice lacking or overexpressing neprilysin in brain. However, the gene dosage of neprilysin did not modulate accumulation of PrPSc in brain. Also, incubation times and clinical course of prion disease, as well as brain infectivity titres at terminal stage, were unaffected. These data rule out neprilysin as a major modulator of PrPSc accumulation and prion pathogenesis.
BackstromJ. R.,
LimG. P.,
CullenM. J.,
TökésZ. A.1996; Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid- β peptide (1-40). J Neurosci 16:7910–7919
BorcheltD. R.,
DavisJ.,
FischerM.8 other authors1996; A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet Anal 13:159–163[CrossRef]
BüelerH.,
FischerM.,
LangY.,
BluethmannH.,
LippH.-P.,
DeArmondS. J.,
PrusinerS. B.,
AguetM.,
WeissmannC.1992; Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356:577–582[CrossRef]
ChenS. G.,
TeplowD. B.,
ParchiP.,
TellerJ. K.,
GambettiP.,
Autilio-GambettiL.1995; Truncated forms of the human prion protein in normal brain and in prion diseases. J Biol Chem 270:19173–19180[CrossRef]
EnariM.,
FlechsigE.,
WeissmannC.2001; Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc Natl Acad Sci U S A 98:9295–9299[CrossRef]
GlatzelM.,
HeppnerF. L.,
AlbersK. M.,
AguzziA.2001; Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31:25–34[CrossRef]
GlatzelM.,
AbelaE.,
MaissenM.,
AguzziA.2003; Extraneural pathologic prion protein in sporadic Creutzfeldt–Jakob disease. N Engl J Med 349:1812–1820[CrossRef]
Jiménez-HueteA.,
LievensP. M. J.,
VidalR.,
PiccardoP.,
GhettiB.,
TagliaviniF.,
FrangioneB.,
PrelliF.1998; Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues. Am J Pathol 153:1561–1572[CrossRef]
KlöhnP.-C.,
StoltzeL.,
FlechsigE.,
EnariM.,
WeissmannC.2003; A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions. Proc Natl Acad Sci U S A 100:11666–11671[CrossRef]
LuhrK. M.,
NordströmE. K.,
LöwP.,
LjunggrenH.-G.,
TaraboulosA.,
KristenssonK.2004; Scrapie protein degradation by cysteine proteases in CD11c+ dendritic cells and GT1-1 neuronal cells. J Virol 78:4776–4782[CrossRef]
PrusinerS. B.,
CochranS. P.,
GrothD. F.,
DowneyD. E.,
BowmanK. A.,
MartinezH. M.1982; Measurement of the scrapie agent using an incubation time interval assay. Ann Neurol 11:353–358[CrossRef]
ShirotaniK.,
TsubukiS.,
IwataN.9 other authors2001; Neprilysin degrades both amyloid β peptides 1-40 and 1-42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases. J Biol Chem 276:21895–21901[CrossRef]
TaraboulosA.,
JendroskaK.,
SerbanD.,
YangS.-L.,
DeArmondS. J.,
PrusinerS. B.1992; Regional mapping of prion proteins in brain. Proc Natl Acad Sci U S A 89:7620–7624[CrossRef]
VincentB.,
PaitelE.,
SaftigP.,
FrobertY.,
HartmannD.,
De StrooperB.,
GrassiJ.,
Lopez-PerezE.,
CheclerF.2001; The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein. J Biol Chem 276:37743–37746