Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol

被引:378
作者
Ma, JY
Wollmann, R
Lindquist, S
机构
[1] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[2] Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA
[3] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
关键词
D O I
10.1126/science.1073725
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 PrPSc isoform and suggests a potential common framework for seemingly diverse PrP neurodegenerative disorders.
引用
收藏
页码:1781 / 1785
页数:5
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