Disturbed vesicular trafficking of membrane proteins in prion disease

Abstract

The pathogenic mechanism of prion diseases remains unknown. We recently reported that prion infection disturbs post-Golgi trafficking of certain types of membrane proteins to the cell surface, resulting in reduced surface expression of membrane proteins and abrogating the signal from the proteins. The surface expression of the membrane proteins was reduced in the brains of mice inoculated with prions, well before abnormal symptoms became evident. Prions or pathogenic prion proteins were mainly detected in endosomal compartments, being particularly abundant in recycling endosomes. Some newly synthesized membrane proteins are delivered to the surface from the Golgi apparatus through recycling endosomes, and some endocytosed membrane proteins are delivered back to the surface through recycling endosomes. These results suggest that prions might cause neuronal dysfunctions and cell loss by disturbing post-Golgi trafficking of membrane proteins via accumulation in recycling endosomes. Interestingly, it was recently shown that delivery of a calcium channel protein to the cell surface was impaired and its function was abrogated in a mouse model of hereditary prion disease. Taken together, these results suggest that impaired delivery of membrane proteins to the cell surface is a common pathogenic event in acquired and hereditary prion diseases.

Keywords: :

• Prion
• prion protein
• post-Golgi membrane trafficking
• insulin receptor
• prion disease
• neurodegeneration
• attractin
• Golgi apparatus

This article refers to:

10.4161/pri.27381

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This study was partly supported by a Grant-in-Aid from the BSE and other Prion Disease Control Project of the Ministry of Agriculture, Forestry and Fisheries of Japan, Grants-in-Aid from the Research Committee of Prion Disease and Slow Virus infection, the Ministry of Health, Labour and Welfare of Japan, and a Grant-in-Aid for TSE research (H23-Shokuhin-Ippan-005) and Research on Measures for Intractable Diseases from the Ministry of Health, Labour and Welfare of Japan. H.M. was partly supported by a Cooperative Research Grant of the Institute for Enzyme Research, The University of Tokushima.