Scrapie-like prion protein accumulates in aggresomes of cyclosporin A-treated cells

Ehud Cohen; Albert Taraboulos

doi:10.1093/emboj/cdg045

Scrapie-like prion protein accumulates in aggresomes of cyclosporin A-treated cells

Ehud Cohen, Albert Taraboulos^*

^*Corresponding author for this work

Department of Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

92 Scopus citations

Abstract

Prion diseases are infectious, sporadic and inherited fatal neurodegenerations that are propagated by an abnormal refolding of the cellular prion protein PrP^C. Which chaperones assist the normal folding of PrP^C is unknown. The linkage of familial Gerstmann-Sträussler-Scheinker (GSS) syndrome with proline substitutions in PrP raised the prospect that peptidylprolyl cis-trans isomerases (PPIases) may play a role in normal PrP metabolism. Here we used cyclosporin A (CsA), an immunosuppressant, to inhibit the cyclophilin family of PPIases in cultured cells. CsA-treated cells accumulated proteasome-resistant, 'prion-like' PrP species, which deposited in long-lived aggresomes. PrP aggresomes also formed with disease-linked proline mutants when proteasomes were inhibited. These results suggest mechanisms whereby abnormally folded cytosolic PrP may in some cases participate in the development of spontaneous and inherited prion diseases.

Original language	English
Pages (from-to)	404-417
Number of pages	14
Journal	EMBO Journal
Volume	22
Issue number	3
DOIs	https://doi.org/10.1093/emboj/cdg045
State	Published - 3 Feb 2003

Keywords

Aggresome
Cyclophilin
Cyclosporin A
Encephalopathy
Prion protein

Access to Document

10.1093/emboj/cdg045

Cite this

@article{2cb3ad87dcbc4f4880497f3ae4c6c242,

title = "Scrapie-like prion protein accumulates in aggresomes of cyclosporin A-treated cells",

abstract = "Prion diseases are infectious, sporadic and inherited fatal neurodegenerations that are propagated by an abnormal refolding of the cellular prion protein PrPC. Which chaperones assist the normal folding of PrPC is unknown. The linkage of familial Gerstmann-Str{\"a}ussler-Scheinker (GSS) syndrome with proline substitutions in PrP raised the prospect that peptidylprolyl cis-trans isomerases (PPIases) may play a role in normal PrP metabolism. Here we used cyclosporin A (CsA), an immunosuppressant, to inhibit the cyclophilin family of PPIases in cultured cells. CsA-treated cells accumulated proteasome-resistant, 'prion-like' PrP species, which deposited in long-lived aggresomes. PrP aggresomes also formed with disease-linked proline mutants when proteasomes were inhibited. These results suggest mechanisms whereby abnormally folded cytosolic PrP may in some cases participate in the development of spontaneous and inherited prion diseases.",

keywords = "Aggresome, Cyclophilin, Cyclosporin A, Encephalopathy, Prion protein",

author = "Ehud Cohen and Albert Taraboulos",

year = "2003",

month = feb,

day = "3",

doi = "10.1093/emboj/cdg045",

language = "אנגלית",

volume = "22",

pages = "404--417",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "Wiley-Blackwell",

number = "3",

}

TY - JOUR

T1 - Scrapie-like prion protein accumulates in aggresomes of cyclosporin A-treated cells

AU - Cohen, Ehud

AU - Taraboulos, Albert

PY - 2003/2/3

Y1 - 2003/2/3

N2 - Prion diseases are infectious, sporadic and inherited fatal neurodegenerations that are propagated by an abnormal refolding of the cellular prion protein PrPC. Which chaperones assist the normal folding of PrPC is unknown. The linkage of familial Gerstmann-Sträussler-Scheinker (GSS) syndrome with proline substitutions in PrP raised the prospect that peptidylprolyl cis-trans isomerases (PPIases) may play a role in normal PrP metabolism. Here we used cyclosporin A (CsA), an immunosuppressant, to inhibit the cyclophilin family of PPIases in cultured cells. CsA-treated cells accumulated proteasome-resistant, 'prion-like' PrP species, which deposited in long-lived aggresomes. PrP aggresomes also formed with disease-linked proline mutants when proteasomes were inhibited. These results suggest mechanisms whereby abnormally folded cytosolic PrP may in some cases participate in the development of spontaneous and inherited prion diseases.

AB - Prion diseases are infectious, sporadic and inherited fatal neurodegenerations that are propagated by an abnormal refolding of the cellular prion protein PrPC. Which chaperones assist the normal folding of PrPC is unknown. The linkage of familial Gerstmann-Sträussler-Scheinker (GSS) syndrome with proline substitutions in PrP raised the prospect that peptidylprolyl cis-trans isomerases (PPIases) may play a role in normal PrP metabolism. Here we used cyclosporin A (CsA), an immunosuppressant, to inhibit the cyclophilin family of PPIases in cultured cells. CsA-treated cells accumulated proteasome-resistant, 'prion-like' PrP species, which deposited in long-lived aggresomes. PrP aggresomes also formed with disease-linked proline mutants when proteasomes were inhibited. These results suggest mechanisms whereby abnormally folded cytosolic PrP may in some cases participate in the development of spontaneous and inherited prion diseases.

KW - Aggresome

KW - Cyclophilin

KW - Cyclosporin A

KW - Encephalopathy

KW - Prion protein

UR - http://www.scopus.com/inward/record.url?scp=0037415754&partnerID=8YFLogxK

U2 - 10.1093/emboj/cdg045

DO - 10.1093/emboj/cdg045

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 12554642

AN - SCOPUS:0037415754

SN - 0261-4189

VL - 22

SP - 404

EP - 417

JO - EMBO Journal

JF - EMBO Journal

IS - 3

ER -

Scrapie-like prion protein accumulates in aggresomes of cyclosporin A-treated cells

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this