TAILIEUCHUNG - Báo cáo khoa học: The reconstitution of mammalian prion infectivity de novo

The discovery of prion disease transmission in mammals, as well as a non-Mendelian type of inheritance in yeast, has led to the establishment of a new concept in biology, the prion hypothesis. The prion hypothesis postu-lates that an abnormal protein conformation propagates itself in an auto-catalytic manner using the normal isoform of the same protein as a substrate and thereby acts either as a transmissible agent of disease (in mammals), | ễFEBS Journal MINIREVIEW The reconstitution of mammalian prion infectivity de novo Ilia V. Baskakov MedicalBiotechnology Center University of Maryland Biotechnology Institute and Department of Biochemistry and Molecular Biology University of Maryland Schoolof Medicine Baltimore MD USA Keywords amyloid fibrils conformationaladaptation in vitro conversion prion diseases prion protein synthetic prions Correspondence I. Baskakov 725 W. Lombard St. Baltimore MD 21201 USA Fax 1 410 706 8184 Tel 1 410 706 4562 E-mail Baskakov@ Received 2 August 2006 revised 30 November 2006 accepted 1 December 2006 doi The discovery of prion disease transmission in mammals as well as a non-Mendelian type of inheritance in yeast has led to the establishment of a new concept in biology the prion hypothesis. The prion hypothesis postulates that an abnormal protein conformation propagates itself in an autocatalytic manner using the normal isoform of the same protein as a substrate and thereby acts either as a transmissible agent of disease in mammals or as a heritable determinant of phenotype in yeast and fungus . While the prion biology of yeast and fungus supports this idea strongly the direct proof of the prion hypothesis in mammals specifically the reconstitution of the disease-associated isoform of the prion protein PrPSc in vitro de novo from noninfectious prion protein has been difficult to achieve despite many years of effort. The present review summarizes our current knowledge about the biochemical nature of the prion infectious agent and structure of PrPSc describes potential strategies for generating prion infectivity de novo and provides some insight on why the reconstitution of infectivity has been difficult to achieve in vitro. Several hypotheses are proposed to explain the apparently low infectivity of the first generation of recently reported synthetic mammalian prions. Prion diseases are a group of fatal neurodegenerative maladies

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