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Down-regulation of shadoo in prion infections traces a pre-clinical event inversely related to PrP sc accumulation
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نویسنده
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westaway d. ,genovesi s. ,daude n. ,brown r. ,lau a. ,lee i. ,mays c.e. ,coomaraswamy j. ,canine b. ,pitstick r. ,herbst a. ,yang j. ,ko k.w.s. ,schmitt-ulms g. ,dearmond s.j. ,mckenzie d. ,hood l. ,carlson g.a.
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منبع
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plos pathogens - 2011 - دوره : 7 - شماره : 11
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چکیده
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During prion infections of the central nervous system (cns) the cellular prion protein,prp c,is templated to a conformationally distinct form,prp sc. recent studies have demonstrated that the sprn gene encodes a gpi-linked glycoprotein shadoo (sho),which localizes to a similar membrane environment as prp c and is reduced in the brains of rodents with terminal prion disease. here,analyses of prion-infected mice revealed that down-regulation of sho protein was not related to sprn mrna abundance at any stage in prion infection. down-regulation was robust upon propagation of a variety of prion strains in prnp a and prnp b mice,with the exception of the mouse-adapted bse strain 301 v. in addition,sho encoded by a tgsprn transgene was down-regulated to the same extent as endogenous sho. reduced sho levels were not seen in a tauopathy,in chemically induced spongiform degeneration or in transgenic mice expressing the extracellular adan amyloid peptide of familial danish dementia. insofar as prion-infected prnp hemizygous mice exhibited accumulation of prp sc and down-regulation of sho hundreds of days prior to onset of neurologic symptoms,sho depletion can be excluded as an important trigger for clinical disease or as a simple consequence of neuronal damage. these studies instead define a disease-specific effect,and we hypothesize that membrane-associated sho comprises a bystander substrate for processes degrading prp sc. thus,while protease-resistant prp detected by in vitro digestion allows post mortem diagnosis,decreased levels of endogenous sho may trace an early response to prp sc accumulation that operates in the cns in vivo. this cellular response may offer new insights into the homeostatic mechanisms involved in detection and clearance of the misfolded proteins that drive prion disease pathogenesis. © 2011 westaway,et al.
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آدرس
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centre for prions and protein folding diseases,university of alberta,edmonton,ab,canada,department of biochemistry,university of alberta,edmonton,ab, Canada, centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, mclaughlin research institute,great falls,mt, United States, centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, institute for systems biology,university of washington,seattle,wa, United States, centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, department of cellular neurology,hertie institute for clinical brain research,university of tuebingen,tuebingen, Germany, mclaughlin research institute,great falls,mt, United States, mclaughlin research institute,great falls,mt, United States, centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, centre for research in neurodegenerative diseases,university of toronto,on,canada,department of laboratory medicine and pathobiology,university of toronto,on, Canada, department of pathology,university of california san francisco,san francisco,ca, United States, centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, institute for systems biology,university of washington,seattle,wa, United States, mclaughlin research institute,great falls,mt, United States
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Authors
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