A Molecular Mechanism for Abnormal Prion Protein Accumulation

*Keiji Uchiyama and Suehiro Sakaguchi*

## **Abstract**

A fundamental event in the pathogenesis of prion disease is the conversion of cellular prion protein into an abnormally folded isoform (PrPSc), which is the infectious causative agent of disease. With progression of disease, PrPSc is replicated and excessively accumulated in most cases. However, the molecular mechanism for excessive accumulation of PrPSc 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 PrPSc degradation. In this chapter, we explain the mechanisms for PrP trafficking into the lysosomal degradation pathway mediated by Sortilin and overaccumulation of PrPSc caused by Sortilin dysfunction.

**Keywords:** PrPSc, PrPSc accumulation, PrPSc degradation, Sortilin, sorting, VPS10P domain, sorting receptor, VPS10P domain receptor

### **1. Introduction**

Prion diseases are a group of fatal neurodegenerative disorders that are caused by the transmissible misfolded isoform (PrPSc) of the cellular prion (PrPC) [1], including Creutzfeldt-Jakob disease of humans, bovine spongiform encephalopathy, and scrapie of sheep. PrPSc is a β-sheet rich conformer of PrPC and is partially resistant to protease. With progression of prion disease, PrPSc is replicated and accumulated in the brain, and neuronal dysfunction and death occur. Previous studies have shown that PrP-null mice neither develop the disease nor accumulate PrPSc even after prions are inoculated into their brains [2, 3]. This indicates that replication and accumulation of PrPSc are closely related to the pathogenesis of prion disease. Therefore, elucidation of the mechanisms of PrPSc degradation and accumulation is critical for understanding the pathogenic mechanism of prion disease and for developing therapeutic agents.

PrPSc usually accumulates excessively over PrPC in cultured cells and mouse brains (**Figure 1**). This strongly indicates that PrPSc is protected against its proteolytic degradation. Actually, several studies have reported that the proteolytic systems (e.g., lysosomal degradation and ubiquitin-proteasomal degradation systems) are inhibited by prion infection [4–7], and PrPSc is found at the cell surface and in endosomal/lysosomal compartments [8–10]. Moreover, when PrPSc was

#### **Figure 1.**

*PrP expression in mice brain and N2a cells. (A) Total PrP and PrPSc were compared between RML prion infected mouse brains at terminal stage and age matched uninfected mice brain by western blotting. (B) N2a cells were treated with uninfected or 22 L-prion infected mice brain homogenate. At 30 dpi, total PrP and PrPSc were detected by western blotting. Blots were probed with anti-PrP antibody (6D11) and anti-*β*-actin antibody.*

fractionated by detergent-based biochemical fractionation, most of the PrPSc was detected in detergent-resistant membrane (DRM) fractions [11], suggesting that PrPSc mainly exists in membrane bound form and PrPSc is degraded preferentially in lysosomes, but not by cytosolic proteasomes. PrPSc to be degraded in lysosomes might be preferentially selected and directed into the lysosomal degradation pathway by dedicated membrane trafficking machinery. Therefore, knowledge of the mechanism that sorts PrP into late endosomal/lysosomal compartments should be important for understanding the accumulation of PrPSc.
