Recognition of lumenal prion protein aggregates by post-ER quality control mechanisms is mediated by the preoctarepeat region of PrP

Sabine Gilch, Max Nunziante, Alexa Ertmer, Franziska Wopfner, L. László, Hermann M. Schätzl

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Prion diseases are fatal transmissible neurodegenerative disorders linked to an aberrant conformation of the cellular prion protein (PrPc). We have shown previously that the chemical compound suramin induced aggregation of fully matured PrPc in post-ER compartments, thereby, activating a post-ER quality control mechanism and preventing cell surface localization of PrP by intracellular re-routing of aggregated PrP from the Golgi/TGN directly to lysosomes. Of note, drug-induced PrP aggregates were not toxic and could easily be degraded by neuronal cells. Here, we focused on determining the PrP domains mediating these effects. Using PrP deletion mutants we show that intracellular re-routing but not aggregation depends on the N-terminal PrP (aa 23-90) and, more precisely, on the preoctarepeat domain (aa 23-50). Fusion of the PrP N-terminus to the GPI-anchored protein Thy-1 did not cause aggregation or re-routing of the chimeric protein, indicating that the N-terminus is only active in re-routing when prion protein aggregation occurs. Insertion of a region with a comparable primary structure contained in the PrP paralogue prnd/doppel (aa 27-50) into N-terminally deleted PrP re-established the re-routing phenotype. Our data reveal an important role for the conserved preoctarepeat region of PrP, namely controlling the intracellular trafficking of misfolded PrP.

Original languageEnglish
Pages (from-to)300-313
Number of pages14
JournalTraffic
Volume5
Issue number4
DOIs
Publication statusPublished - Apr 2004

Fingerprint

Quality Control
Quality control
Agglomeration
Suramin
Prion Diseases
Poisons
Lysosomes
Neurodegenerative Diseases
Proteins
Phenotype
Chemical compounds
Prions
Pharmaceutical Preparations
Conformations
Fusion reactions
Protein Aggregates
Prion Proteins

Keywords

  • Preoctarepeat
  • Prion disease
  • PrP
  • Quality control
  • Re-routing

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Structural Biology
  • Molecular Biology
  • Genetics

Cite this

Recognition of lumenal prion protein aggregates by post-ER quality control mechanisms is mediated by the preoctarepeat region of PrP. / Gilch, Sabine; Nunziante, Max; Ertmer, Alexa; Wopfner, Franziska; László, L.; Schätzl, Hermann M.

In: Traffic, Vol. 5, No. 4, 04.2004, p. 300-313.

Research output: Contribution to journalArticle

Gilch, Sabine ; Nunziante, Max ; Ertmer, Alexa ; Wopfner, Franziska ; László, L. ; Schätzl, Hermann M. / Recognition of lumenal prion protein aggregates by post-ER quality control mechanisms is mediated by the preoctarepeat region of PrP. In: Traffic. 2004 ; Vol. 5, No. 4. pp. 300-313.
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