Dubiknov, Tatyana, Hoepfner, Dominic and Cohen, Ehud (2016) The Triage of Misfolded Prion Molecules to Aggresomes Occurs Within the Endoplasmic Reticulum. Journal of cell science, 129 (19). pp. 3635-3647. ISSN 1477-9137; 0021-9533

Abstract

To mature properly, nascent prion protein (PrP) molecules undergo a series of chaperone-assisted, folding events and post-translational modifications within the endoplasmic reticulum (ER). Neurodegeneration-linked proline substitutions in the PrP sequence prevent folding chaperones of the cyclophilin family from assisting the protein to mature properly, leading to its aggregation and deposition in cytosolic compartments known as "aggresomes". The prerequisites for directing misfolded PrP species to this structure are largely obscure. Here we investigated the mechanism that directs misfolded PrP molecules to the aggresome and found that they must enter the endoplasmic reticulum (ER) and acquire a glycosylphosphatidyl inositol (GPI) anchor in order to be deposited in these structures. In contrast, the Golgi apparatus plays no role in this process. Our results point at the ER-resident cyclophilin B as a crucial player in the maturation of PrP, indicate that an ER quality control mechanism governs aggresome formation and highlight the counter-proteotoxic roles of this organelle.

Item Type:	Article
Date Deposited:	12 Oct 2016 00:45
Last Modified:	12 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/26515