Melanin or a melanin-like substance interacts with the N-terminal portion of prion protein and inhibits abnormal prion protein formation in prioninfected cells

Taichi Hamanaka, Keiko Nishizawa, Yuji Sakasegawa, Ayumi Oguma, Kenta Teruya, Hiroshi Kurahashi, Hideyuki Hara, Suehiro Sakaguchi, Katsumi Doh-Ura

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecularweight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-L-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanininjected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear.

Original languageEnglish
Article numbere01862-16
JournalJournal of virology
Volume91
Issue number6
DOIs
Publication statusPublished - 2017

Keywords

  • Drug discovery
  • Mechanisms of action
  • Melanin
  • Prions

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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