Open access peer-reviewed chapter

A Molecular Mechanism for Abnormal Prion Protein Accumulation

Written By

Keiji Uchiyama and Suehiro Sakaguchi

Submitted: 07 May 2018 Reviewed: 20 May 2018 Published: 05 November 2018

DOI: 10.5772/intechopen.78951

From the Edited Volume

Prions - Some Physiological and Pathophysiological Aspects

Edited by Ivo Nikolaev Sirakov

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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.


  • 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, 5, 6, 7], and PrPSc is found at the cell surface and in endosomal/lysosomal compartments [8, 9, 10]. Moreover, when PrPSc was 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.

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.


2. PrPSc accumulation

Figure 1A shows the expression of total PrP and PrPSc in uninfected and prion-infected mouse brains. In this figure, we can easily recognize that the total amount of PrP in infected mouse brains is larger than in uninfected mouse brains. In cultured cells, such excessive expression of total PrP in infected cells was also confirmed ( Figure 1B ). These results indicate that the amount of PrPSc in infected cells is larger than PrPC in uninfected cells, and that PrPSc is protected against proteolytic degradation.

Why is PrPSc protected from proteolysis and over-accumulated? One possible reason is the protease resistance of PrPSc that is attributed to its β-rich structure at the C-terminal region. If such protease resistance mainly affected the inhibition of PrPSc degradation, most of the PrPSc could be found in the lysosome, which contains various kinds of hydrolytic enzymes and is a major compartment responsible for the digestion of macromolecules such as proteins. The majority of PrPSc is actually observed intracellularly, whereas PrPC mainly localizes to the cell surface ( Figure 2A ). However, detailed analyses of its intracellular distribution show that PrPSc is widely distributed in posttrans Golgi network (TGN) compartments [8, 9, 10] ( Figure 2B ). From these observations, it seems that impairment of PrPSc trafficking into lysosomes as well as its protease-resistance causes inhibition of degradation and over-accumulation of PrPSc.

Figure 2.

PrPSc is widely distributed in post-Golgi compartments. (A) PrPC (green, uninfected cells) and PrPSc (green, infected cells) were visualized by immunofluorescence staining with mouse monoclonal anti-PrP antibody (SAF83) and anti-PrPSc antibody (132), respectively. (B) PrPSc indicated organelle markers in prion infected cells were doubly stained with anti-PrPSc antibody (132) and anti-transferrin receptor, Rab11, Rab5, Rab9 and LAMP1 antibody, respectively. DAPI was used for nuclear stain (blue).


3. Sortilin and other VPS10P domain receptors

PrP would have to move by transport vesicles in post-TGN compartments, including TGN, endosomes, lysosomes, and the plasma membrane. Then, in this transport network, the PrP to be degraded could be sorted into transport carriers bound for late endosomal/lysosomal compartments. For this purpose, a sorting receptor might be useful and required because it can select and concentrate a target cargo protein into transport carriers and promote transport carrier formation. In our recent study, Sortilin has been identified as a sorting receptor that directs PrP into late endosomal/lysosomal compartments. Sortilin is a member of the VPS10P domain receptor family, which is comprised of five members (Sortilin, SorCS1, SorCS2, SorCS3, and SorLA). In this section, briefly, we describe Sortilin and other VPS10P receptors and their implications for neurodegenerative diseases.

VPS10P-domain receptors are multiligand type-I transmembrane proteins. They contain five members, Sortilin, SorLA, SorCS1, SorCS2, and SorCS3, and deliver a number of target cargo proteins to their destinations, interacting with them via VPS10P domains on the luminal/extracellular N-terminus ( Figure 3 ). The whole luminal/extracellular region in Sortilin is composed of a simple VPS10P domain, but other receptors have additional modules ( Figure 3 ).

Figure 3.

VPS10P domain receptors. VPS10P-domain receptors are multiligand type-I transmembrane proteins. They contain five members, Sortilin, SorLA, SorCS1, SorCS2 and SorCS3. The extracellular/luminal region of VPS10P receptors contains VPS10P domain and additional domains. The intracellular domain of VPS10P receptors contains motifs for interaction with adaptor proteins. The propeptide at N-terminal region is cleaved by furin in the TGN.

VPS10P-domain receptors are expressed in the brain and are involved in neuronal function and viability [12, 13]. Sortilin binds to progranulin and mediates endocytosis and delivery of progranulin into lysosomes [14], and rare nonsynonymous variants in SORT1 increase the risk for frontotemporal lobar degeneration [15]. Sortilin also mediates trafficking of neuronal degeneration causative and related proteins. Sortilin has been identified as an amyloid precursor protein (APP) interaction partner and promotes α-cleavage of APP [16]. In addition, Sortilin interacts with BACE1, β-site APP cleavage enzyme 1, and mediates its retrograde trafficking from the plasma membrane to TGN via early endosomes [17]. It has been suggested that Sortilin is potentially associated with Parkinson’s disease [18]. Moreover, recently, it has been reported that Sortilin is involved in tau prion replication [19].

As for other VPS10P receptors, it has been reported that SorLA is associated with sporadic and late-onset Alzheimer’s disease (AD) [5, 20]. SorLA directs APP into the recycling pathway and protects APP from β-cleavage resulting in Aβ generation [5, 21, 22]. On the other hand, loss of SorLA shifts the traffic flow of APP to the late endosomal pathway and facilitates β-cleavage of APP and Aβ-generation [5, 21, 22]. In addition, a meta-analysis indicated that multiple SorLA variants are associated with the risk of Alzheimer’s disease [23]. SorCS1 is also involved in APP transport and Aβ-generation and is identified as a risk factor for Alzheimer’s disease [24, 25]. Variants of SorCS2 and SorCS3 are also associated with the risk of Alzheimer’s disease [24, 25]. Although a number of studies have indicated that VPS10P-domain receptors are implicated in neurodegenerative diseases and their impairment could be a risk factor for diseases, the relation between VPS10P receptors and prion disease is not known.


4. Role of Sortilin in PrP trafficking

Sortilin has been identified as a novel PrP-binding protein and is colocalized with PrPC both at the cell surface and intracellular compartments [11]. In Sortilin-knockdown (Sortilin-KD) uninfected cells, most of the PrPC is localized at the cell surface, and PrPC expression is increased. In addition, a PrPC uptake experiment, in which cell surface PrPC was labeled with anti-PrP antibody and internalized labeled PrPC was measured after incubation, demonstrated that PrPC internalization was weakened by Sortilin-KD [11]. These results indicate that Sortilin acts as a cell surface receptor for PrPC endocytosis.

PrPC was also colocalized with Sortilin intracellularly [11]. This made us recollect that Sortilin could function intracellularly as a sorting receptor for PrP trafficking. When the internalized labeled PrPC was costained for either Rab9 (a late endosomal marker) or Rab11 (a recycling endosomal marker) by indirect immunofluorescence, the internalized PrPC distributed to both late and recycling endosomes in control cells, whereas, in Sortilin-depleted cells, it failed to localize to late endosomes, and most of the internalized PrPC is localized to recycling endosomes [11]. These observations indicate that Sortilin is also required for sorting of PrPC into late endosomes to degrade it.

Moreover, when wild type (wt) and Sortilin-knockout (ΔSort) cells were treated with NH4Cl, which increases lysosomal pH and inhibits proteolytic enzymes in lysosomes, PrPC was effectively accumulated in wt but not in ΔSort cells [11], and PrPC colocalization with LAMP1, a lysosomal marker, in NH4Cl-treated ΔSort cells was significantly lower than NH4Cl-treated wt cells [11]. These results suggest that ΔSort cells failed to transport PrPC properly into lysosomes.

Altogether, it could be concluded that Sortilin functions as a cell surface receptor for PrPC internalization and a sorting receptor to direct PrPC to lysosomes via late endosomes ( Figure 4 ). We would be able to extend such a role of Sortilin in PrPC trafficking to PrPSc because Sortilin directly interacted with PrPC through its highly flexible N-terminal domain and anti-Sortilin antibody coprecipitated both PrPC and PrPSc. In practical terms, Sortilin is implicated in PrPSc degradation.

Figure 4.

Role of Sortilin in PrP-trafficking. Sortilin internalizes PrP from nonraft domain and direct into late endosomal/lysosomal degradation pathway. PrP internalized from lipid raft domain in Sortilin-independent manner would be largely recycled into cell surface. PrP might be also internalized from nonraft domain in Sortilin-independent manner. Red arrows indicate Sortilin mediated PrP-trafficking pathway. Blue line is lipid raft domain. EE: Early endosome, LE: Late endosomes, RE: Recycling endosomes, Lys: Lysosomes, PM: Plasma membrane.

The inhibition of Sortilin inhibited PrPC internalization by ~20% in the PrPC uptake assay [11]. This result raises a question. Why is PrPC endocytosis inhibited partially even when Sortilin function is almost or completely abolished [11]? There are suggestive findings to answer this question. We examined the PrP distribution in uninfected wt cells and in uninfected ΔSort cells by detergent-based biochemical fractionation. Sixty three percent of PrPC in wt cells was detected in detergent resistant membrane (DRM) fractions, generally recognized as raft fractions, but thirty-seven percent of PrPC was also found in detergent soluble (nonraft) fractions [11]. Sortilin deficiency changed the PrPC distribution, and PrPC in nonraft fractions was reduced to ~15% in ΔSort cells [11]. At present, it is thought that both lipid raft- and clathrin-mediated endocytosis execute PrPC internalization [13, 26]. Sortilin was mostly isolated in nonraft fractions [11]. It has been reported that the cytoplasmic tail of Sortilin can interact with clathrin-associated adaptor protein complex, AP-2, at the plasma membrane and facilitate clathrin-mediated endocytosis [13, 27, 28]. We showed that the recombinant PrP devoid of its N-terminal domain (residues 23–88) (PrPΔ23–88) did not bind to Sortilin. Additionally, internalization and lysosomal degradation of PrPΔ23–88 were inhibited, and it accumulated at the cell surface [11]. These results are in good agreement with a previous report: the N-terminal domain (residues 23–107) of PrPC is sufficient for its endocytosis mediated by clathrin [29]. It is therefore inferred that Sortilin internalizes PrPC from nonraft domains at the cell surface by clathrin-coated vesicles. Moreover, it has been shown that the expression of total PrPC was not changed even when the flotillin-1–mediated lipid raft-dependent endocytosis of PrPC was inhibited by the knockdown of flotillin-1 [30]. Their and our results suggest that Sortilin-mediated endocytosis directs PrPC into the late endosomal/lysosomal degradation pathway, whereas PrPC that is internalized from the lipid raft domain in a Sortilin-independent manner largely enters the recycling pathway ( Figure 4 ).


5. Dysfunction of Sortilin by prion infection

Sortilin expression also affects PrPSc levels. Sortilin-KD increased PrPSc in prion infected cells, similarly to PrPC in uninfected cells [11]. On the contrary, overexpression of Sortilin in infected cells reduced PrPSc [11]. Furthermore, when we investigated PrPSc accumulation in Sort1+/+ and Sort1−/− mouse brains after intracerebral prion inoculation, PrPSc levels in Sort1−/− mouse brains were significantly higher than in Sort1+/+ mouse brains at the early stages of disease (at 45, 60, 90 dpi) [11], suggesting an inhibition of PrPSc degradation. Namely, dysfunction of Sortilin causes excessive accumulation. If so, does prion infection inhibit Sortilin function? Notably, Sortilin in infected cells was ~50% lower than in uninfected cells [11]. Moreover, in infected mouse brains at terminal stage, Sortilin also fell to ~45% as compared with age-matched uninfected mice [11]. These observations suggested that prion infection downregulated Sortilin expression. To confirm this, uninfected cells were treated with RML prion-infected mouse brain homogenate, and Sortilin and PrPSc in individual cells were visualized by double immunofluorescence staining at 9 dpi ( Figure 5 ). In cells displaying bright green signals derived from PrPSc, little Sortilin (red) was detected, whereas the bright red fluorescence of Sortilin was observed in the others; that is, Sortilin expression was reduced by prion infection.

Figure 5.

Prion infection reduces Sortilin expression. Immunofluorescence staining of Sortilin (red) and PrPSc (green) 9 days after infection of uninfected cells with RML prions. Four horizontal serial images at 1 μm interval were collected, and orthogonally projected image was created. DAPI was used for nuclear stain (blue). Yellow arrow indicates PrPSc-positive cell.

To clarify why Sortilin is reduced by prion infection, we examined mRNA transcript levels by RT-PCR. There was little difference in Sortilin mRNA abundance between uninfected and infected cells. This suggested that the degradation of Sortilin was facilitated in prion infected cells. Hence, we treated cells with inhibitors of proteolytic degradation. The expression of Sortilin was almost the same in both untreated and MG132-treated cells but increased in NH4Cl-treated cells [11]. In particular, Sortilin expression was dramatically improved in NH4Cl-treated prion-infected cells, and another lysosomal inhibitor, concanamycin A, also improved Sortilin expression in infected cells [11], suggesting that Sortilin is over-degraded in prion-infected cells in lysosomes.


6. Conclusions

Sortilin has been identified as a novel PrP-binding protein and functions as a sorting receptor to direct PrP into late endosomal/lysosomal compartments. Dysfunction of Sortilin induces delayed degradation and excessive accumulation of PrP. Notably, prion infection downregulated Sortilin expression by facilitating Sortilin degradation in lysosomes. Finally, we summarize a possible mechanism of excessive accumulation of PrPSc during prion infection ( Figure 6 ): (I) the entry of Sortilin into the lysosomal degradation pathway is facilitated by prion infection, (II) Sortilin is over-degraded in lysosomes, (III) trafficking of PrPSc to late endosomal/lysosomal compartments is restricted, and (IV) PrPSc is protected against its degradation in lysosomes and is excessively accumulated. However, it still remains unclear how prion infection facilitates Sortilin degradation in lysosomes.

Figure 6.

Possible mechanism for PrPSc over-accumulation by prion infection. (I) the entry of Sortilin into the lysosomal degradation pathway is facilitated (green arrow) by prion infection (yellow arrow), (II) Sortilin is over-degraded in lysosomes, (III) trafficking of PrPSc to late endosomal/lysosomal compartments is restricted (red broken arrow), and (IV) PrPSc is protected against its degradation in lysosomes and is excessively accumulated. Red arrows indicate Sortilin-mediated PrP-trafficking pathway and blue arrows indicate other PrP-trafficking pathways. EE: Early endosomes, LE: Late endosomes, RE: Recycling endosomes, Lys: Lysosomes, PM: Plasma membrane.



This work was supported by the following: Pilot Research Support Program in Tokushima University received by KU; Naito Foundation received by KU; JSPS KAKENHI grant (grant No. 26460557, received by KU; MEXT KAKENHI grant (grant No, 17H05702, received by KU; JSPS KAKENHI grant (grant No. 26293212, received by SS; MEXT KAKENHI grant (grant No, 15H01560 and 17H05701, received by SS; and Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (AMED) received by SS.


Conflict of interest

The authors have declared that no competing interests exist.


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Written By

Keiji Uchiyama and Suehiro Sakaguchi

Submitted: 07 May 2018 Reviewed: 20 May 2018 Published: 05 November 2018