Prion Protein Gene Variation Among Primates

Schätzl, Hermann; Costa, Maria Da; Taylor, Leslie M.; Cohen, Fred E.; Prusiner, Stanley B.

doi:10.1006/jmbi.1994.0030

Cited by 307 publications

(155 citation statements)

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“…Phylogenetically, methionine is the ancestral amino acid at codon 129 (52), and Val 129 is a mutation found in humans. Worldwide PRNP haplotype diversity and coding allele frequencies suggest that strong balancing selection at this locus occurred during the evolution of modern human and made heterozygosity at PRNP a significant selective advantage (53).…”

Section: Discussionmentioning

confidence: 99%

Methionine 129 Variant of Human Prion Protein Oligomerizes More Rapidly than the Valine 129 Variant

Tahiri-Alaoui

Gill

Disterer

et al. 2004

Journal of Biological Chemistry

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The human PrP gene (PRNP) has two common alleles that encode either methionine or valine at codon 129. This polymorphism modulates disease susceptibility and phenotype of human transmissible spongiform encyphalopathies, but the molecular mechanism by which these effects are mediated remains unclear. Here, we compared the misfolding pathway that leads to the formation of ␤-sheet-rich oligomeric isoforms of the methionine 129 variant of PrP to that of the valine 129 variant. We provide evidence for differences in the folding behavior between the two variants at the early stages of oligomer formation. We show that Met 129 has a higher propensity to form ␤-sheet-rich oligomers, whereas Val 129 has a higher tendency to fold into ␣-helical-rich monomers. An equimolar mixture of both variants displayed an intermidate folding behavior. We show that the oligomers of both variants are initially a mixture of ␣-and ␤-rich conformers that evolve with time to an increasingly homogeneous ␤-rich form. This maturation process, which involves no further change in proteinase K resistance, occurs more rapidly in the Met 129 form than the Val 129 form. Although the involvement of such ␤-rich oligomers in prion pathogenesis is speculative, the misfolding behavior could, in part, explain the higher susceptibility of individuals that are methionine homozygote to both sporadic and variant CreutzfeldtJakob disease.

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Section: Discussionmentioning

confidence: 99%

Methionine 129 Variant of Human Prion Protein Oligomerizes More Rapidly than the Valine 129 Variant

Tahiri-Alaoui

Gill

Disterer

et al. 2004

Journal of Biological Chemistry

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“…The Prnp gene is conserved in mammals (27), and paralogues are present in turtle (28), fish (29,30), and amphibians (31), suggesting an important function of PrP C . No natural Prnp null alleles were described despite negative evolutionary pressure (32).…”

Section: Discussionmentioning

confidence: 99%

Disruption of Doppel prevents neurodegeneration in mice with extensive Prnp deletions

Genoud¹,

Behrens²,

Miele³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…An amino acid Y-to-F substitution was found at codon 6 in the signal sequence, and a heterozygous base was found at codon 103 (encoding both S and N). In addition, Turkish hamsters have a deletion of 1 octapeptide repeat (Δ81-87) on both alleles, a characteristic shared with African Green monkeys (32). In humans, deletion of 1 octapeptide repeat occurs at a frequency of 0.5% and is not associated with disease (33,34).…”

Section: Sequencingmentioning

confidence: 99%

Characteristics of 263K Scrapie Agent in Multiple Hamster Species

Meade-White

Barbian²,

Race³

et al. 2009

Emerg. Infect. Dis.

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Transmissible spongiform encephalopathy (TSE) diseases are known to cross species barriers, but the pathologic and biochemical changes that occur during transmission are not well understood. To better understand these changes, we infected 6 hamster species with 263K hamster scrapie strain and, after each of 3 successive passages in the new species, analyzed abnormal proteinase K (PK)-resistant prion protein (PrPres) glycoform ratios, PrPres PK sensitivity, incubation periods, and lesion profi les. Unique 263K molecular and biochemical profi les evolved in each of the infected hamster species. Characteristics of 263K in the new hamster species seemed to correlate best with host factors rather than agent strain. Furthermore, 2 polymorphic regions of the prion protein amino acid sequence correlated with profi le differences in these TSE-infected hamster species.

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Prion Protein Gene Variation Among Primates

Cited by 307 publications

References 0 publications

Methionine 129 Variant of Human Prion Protein Oligomerizes More Rapidly than the Valine 129 Variant

Methionine 129 Variant of Human Prion Protein Oligomerizes More Rapidly than the Valine 129 Variant

Disruption of Doppel prevents neurodegeneration in mice with extensive Prnp deletions

Characteristics of 263K Scrapie Agent in Multiple Hamster Species

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