A Pathogenic PrP Mutation and Doppel Interfere with Polarized Sorting of the Prion Protein*
- ‡Adolf Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany, the §Max-Planck-Institute for Biochemistry, Department of Cellular Biochemistry, 82152 Martinsried, Germany, and the ¶Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland
- ↵∥ To whom correspondence should be addressed: Dept. of Cellular Biochemistry, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany. Fax: 49-89-8578-2211; E-mail: winklhof{at}biochem.mpg.de.
Abstract
Several proteins linked to neurodegenerative diseases, such as the β-amyloid precursor protein, amyloid β-peptide, β-secretase, and tau, undergo selective polarized sorting. We investigated polarized sorting of the mammalian prion protein (PrPC) and its homologue doppel (Dpl). In contrast to Dpl, which accumulates on the apical surface, PrPC is targeted selectively to the basolateral side in Madin-Darby canine kidney cells. An extensive deletion and domain swapping analysis revealed that the internal hydrophobic domain (HD) of PrP (amino acids 113–133) confers basolateral sorting in a dominant manner. PrP mutants lacking the HD are sorted apically, while Dpl chimeras containing the HD of PrP are directed to the basolateral membrane. Furthermore, a pathogenic PrP missense mutation within the HD leads to aberrant apical sorting of PrP as well.
- Received December 2, 2004.
- Revision received December 14, 2004.
- The American Society for Biochemistry and Molecular Biology, Inc.
