DOI: 10.1126/science.1073725. Neurotoxicity and Neurodegeneration When PrP Accumulates in the Cytosol

Neurotoxicity and Neurodegeneration When PrP Accumulates in the Cytosol

10.1126/science.1073725

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Changes in prion protein (PrP) folding are associated with fatal neurodegenerative disorders, but the neurotoxic species is unknown. Like other proteins that traffic through the endoplasmic reticulum, misfolded PrP is retrograde transported to the cytosol for degradation by proteasomes. Accumulation of even small amounts of cytosolic PrP was strongly neurotoxic in cultured cells and transgenic mice. Mice developed normally but acquired severe ataxia, with cerebellar degeneration and gliosis. This establishes a mechanism for converting wild-type PrP to a highly neurotoxic species that is distinct from the self-propagating PrP Sc isoform and suggests a potential common framework for seemingly diverse PrP neurodegenerative disorders.

Bibliography

Ma, J., Wollmann, R., & Lindquist, S. (2002). Neurotoxicity and Neurodegeneration When PrP Accumulates in the Cytosol. Science, 298(5599), 1781â1785.

Authors 3

Jiyan Ma (first)
Robert Wollmann (additional)
Susan Lindquist (additional)

References 52 Referenced 398

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; published online 17 October 2002 (10.1126/science.1073619).
Cytomegalovirus promoter.
Experiments were performed as in (14).
Materials and methods are available as supporting materials on Science Online.
First unglycosylated proteins are more likely to misfold in the ER and be subject to retrograde transport; second glycosylated species that are retrograde transported are subject to cytoplasmic deglycosidases.
10.1146/annurev.biochem.69.1.69
10.1083/jcb.149.5.1039
J. Ma R. Wollmann S. Lindquist data not shown.
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Chesebro B., et al., Dev. Biol. Stand. 80, 131 (1993). / Dev. Biol. Stand. by Chesebro B. (1993)
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More than 50% of N2A cells died within 12 hours of proteasome treatment but less than 5% of moPrP cells died during the same period.
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Supporting text and data are available on Science Online.
Slow growth might be due to ataxia-associated problems with eating and drinking although special care was taken to provide accessible food and water.
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In a related manner our model explains the puzzling ability of certain neuroblastoma lines to continuously produce PrP Sc without dying. In these cells PrP Sc conversion appears to occur solely on the cell surface and in endocytic compartments.
10.1016/S0021-9258(18)55257-1
10.1128/jvi.74.10.4894-4897.2000
We thank B. Caughey G. Thinakaran and J. Tatzelt for providing cell lines and antibodies; X. Wang Y. Wang and E. Rehm for technical help; members of the Lindquist lab for critical reading of this manuscript; and NIH (GM25874) and the Howard Hughes Medical Institute for funding this research. This work was initiated in S.L.'s laboratory at the University of Chicago and continued there under her supervision after her move to the Whitehead Institute for Biomedical Research.

Dates

Type	When
Created	22 years, 8 months ago (Nov. 29, 2002, 10:32 a.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 9:03 p.m.)
Indexed	1 week, 1 day ago (Aug. 19, 2025, 6:46 a.m.)
Issued	22 years, 8 months ago (Nov. 29, 2002)
Published	22 years, 8 months ago (Nov. 29, 2002)
Published Print	22 years, 8 months ago (Nov. 29, 2002)

Funders 0

None

BibTeX

@article{Ma_2002, title={Neurotoxicity and Neurodegeneration When PrP Accumulates in the Cytosol}, volume={298}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1073725}, DOI={10.1126/science.1073725}, number={5599}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Ma, Jiyan and Wollmann, Robert and Lindquist, Susan}, year={2002}, month=nov, pages={1781–1785} }

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