Selective re-routing of prion protein to proteasomes and alteration of its vesicular secretion prevent PrP(Sc) formation.

Abstract:

:Conversion of the cellular prion protein (PrP(C)) into the abnormal scrapie isoform (PrP(Sc)) is the hallmark of prion diseases, which are fatal and transmissible neurodegenerative disorders. ER-retained anti-prion recombinant single-chain Fv fragments have been proved to be an effective tool for inhibition of PrP(C) trafficking to the cell surface and antagonize PrP(Sc) formation and infectivity. In the present study, we have generated the secreted version of 8H4 intrabody (Sec-8H4) in order to compel PrP(C) outside the cells. The stable expression of the Sec-8H4 intrabodies induces proteasome degradation of endogenous prion protein but does not influence its glycosylation profile and maturation. Moreover, we found a dramatic diverting of PrP(C) traffic from its vesicular secretion and, most importantly, a total inhibition of PrP(Sc) accumulation in NGF-differentiated Sec-8H4 PC12 cells. These results confirm that perturbing the intracellular traffic of endogenous PrP(C) is an effective strategy to inhibit PrP(Sc) accumulation and provide convincing evidences for application of intracellular antibodies in prion diseases.

journal_name

J Neurochem

authors

Filesi I,Cardinale A,Mattei S,Biocca S

doi

10.1111/j.1471-4159.2006.04439.x

subject

Has Abstract

pub_date

2007-06-01 00:00:00

pages

1516-26

issue

6

eissn

0022-3042

issn

1471-4159

pii

JNC4439

journal_volume

101

pub_type

杂志文章