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演題詳細

Symposium

Brain Proteinopathy 2014
Brain Proteinopathy 2014

開催日 2014/9/11
時間 17:00 - 19:00
会場 Room E(301)
Chairperson(s) 田中 元雅 / Motomasa Tanaka (独立行政法人理化学研究所 脳科学総合研究センター タンパク質構造疾患研究チーム / Laboratory for Protein Conformation Diseases, RIKEN Brain Science Institute, Japan)
貫名 信行 / Nobuyuki Nukina (順天堂大学大学院医学研究科 神経変性疾患病態治療探索講座 / Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Japan)

酵母プリオンは環境ストレスに対する適応性の獲得を促進させる
Yeast prion promotes acquired cellular adaptation to environmental stress

  • S1-E-3-2
  • 田中 元雅 / Motomasa Tanaka:1 
  • 1:独立行政法人理化学研究所 / RIKEN Brain Science Institute, Japan 

Prions are protein-based transmissible elements that undergo conformational changes resulting in the formation of amyloid, beta-sheet-rich fibrillar aggregates observed in many neurodegenerative diseases. Recent studies have expanded our understanding of the tropism and adaptation of prion conversion to selective pressure in the surrounding environment. However, it remains unknown whether and how prion states actively respond to environmental stress and acquire a survival advantage under selective pressure. Here we identified Mod5, a yeast transfer RNA isopentenyltransferase as a new class of yeast prion protein lacking glutamine/asparagine-rich domains and found that Mod5 responded to an environmental stressor by converting to amyloid consequent to phenotypic changes in cell metabolism and drug resistance. Introduction of Mod5 amyloid into yeast resulted in the formation of a dominantly heritable prion state [MOD+], in which Mod5 is aggregated, in contrast to soluble Mod5 found in a non-prion [mod-] state. [MOD+] yeast contained high ergosterol levels indicative of a shift in cell metabolic state and acquired drug resistance to several anti-fungal agents. Remarkably, selective pressure by anti-fungal drugs on non-prion [mod-] yeast induced the [MOD+] prion state with formation of amyloid and increased cell survival. Taken together, these results establish that endogenous cellular Mod5 can respond to positive selection in the environment by converting to an amyloid state and altering cellular phenotype to gain a survival advantage. These findings suggest that endogenous prion conversion in response to environmental selection may be responsible for a broader spectrum of cellular adaptation in living systems than previously recognized, including a potential mechanism for biodiversity in agriculture and drug resistance in medicine. Furthermore, these results introduce the hypothesis that conformational conversion of a protein to amyloid in some forms of neurodegeneration may represent an adaptive mechanism for survival in response to stress from the cellular environment.

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