Synthetic fibril peptide promotes clearance of scrapie prion protein by lysosomal degradation.
Transmissible spongiform encephalopathies are infectious and neurodegenerative disorders that cause neural deposition of aggregates of the disease-associated form of PrP(Sc). PrP(Sc) reproduces by recruiting and converting the cellular PrP(C), and ScN2a cells support PrP(Sc) propagation. We found that incubation of ScN2a cells with a fibril peptide named P9, which comprises an intrinsic sequence of residues 167-184 of mouse PrP(C), significantly reduced the amount of PrP(Sc) in 24 hr. P9 did not affect the rates of synthesis and degradation of PrP(C). Interestingly, immunofluorescence analysis showed that the incubation of ScN2a cells with P9 induced colocalization of the accumulation of PrP with cathepsin D-positive compartments, whereas the accumulation of PrP in the cells without P9 colocalized mainly with lysosomal associated membrane proteins (LAMP)-1-positive compartments but rarely with cathepsin D-positive compartments in perinuclear regions. Lysosomal enzyme inhibitors attenuated the anti-PrP(Sc) activity; however, a proteasome inhibitor did not impair P9 activity. In addition, P9 neither promoted the ubiquitination of cellular proteins nor caused the accumulation of LC3-II, a biochemical marker of autophagy. These results indicate that P9 promotes PrP(Sc) redistribution from late endosomes to lysosomes, thereby attaining PrP(Sc) degradation.
Okemoto-Nakamura
Yuko
Y
Department of Biochemistry and Cell Biology, National Institue of Infectious Diseases, Tokyo, Japan.
Yamakawa
Yoshio
Y
Hanada
Kentaro
K
Tanaka
Keiko
K
Miura
Masami
M
Tanida
Isei
I
Nishijima
Masahiro
M
Hagiwara
Ken'ichi
K
D000595:Amino Acid Sequence; D000818:Animals; D002402:Cathepsin D / Q000032:analysis; D011992:Endosomes / Q000737:chemistry; D051907:Lysosomal Membrane Proteins / Q000032:analysis; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism*; D018622:PrP 27-30 Protein / Q000138:chemical synthesis* / Q000276:immunology*; D018620:PrPSc Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D052118:Lysosomal-Associated Membrane Protein 1
D002402:Cathepsin D; D051907:Lysosomal Membrane Proteins; D010455:Peptides; D018622:PrP 27-30 Protein; D018620:PrPSc Proteins; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1