A Molecular Mechanism for Abnormal Prion Protein Accumulation

A fundamental event in the pathogenesis of prion disease is the conversion of cellular prion protein into an abnormally folded isoform (PrP Sc ), which is the infectious causative agent of disease. With progression of disease, PrP Sc is replicated and excessively accumulated in most cases. However, the molecular mechanism for excessive accumulation of PrP Sc is not well understood. Recently, Sortilin, a member of the VPS10P domain receptor family, has been identified as a sorting receptor that directs prion protein (PrP) to the lysosomal degradation pathway. Moreover, it has been shown that prion infection impairs Sortilin function, resulting in delayed PrP Sc degradation. In this chapter, we explain the mechanisms for PrP trafficking into the lysosomal degradation pathway mediated by Sortilin and overaccumulation of PrP Sc caused by Sortilin dysfunction.