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. Author manuscript; available in PMC: 2020 May 13.
Published in final edited form as: Curr Opin Pharmacol. 2019 May 13;44:46–52. doi: 10.1016/j.coph.2019.04.013

Autophagy pathways in the treatment of prion diseases

Dalia H Abdelaziz a,b,c,, Basant A Abdulrahman a,b,c,, Sabine Gilch a,b,d, Hermann M Schatzl a,b,c,*
PMCID: PMC6610235  NIHMSID: NIHMS1527555  PMID: 31096117

Abstract

Prions use cellular machineries for autocatalytic propagation by conformational conversion of the cellular prion protein into the pathological isoform PrPSc. Autophagy is a basic cellular degradation and recycling machinery that delivers cargo to lysosomes. Increase of autophagic flux in cells results in enhanced delivery of PrPSc in late endosomes to lysosomal degradation, providing a therapeutic target for prion diseases. Application of chemical enhancers of autophagy to cell or mouse models of prion infection provided a solid experimental proof-of-concept for this anti-prion strategy. In addition, increasing autophagy also reduces exosomal release of prions and transfer of prion infectivity between cells. Taken together, pharmacological induction of autophagy is a promising target for containing prion diseases, and ideal candidate for future combination therapies.

Introduction

Prion diseases are fatal infectious neurodegenerative disorders of man and animals which are characterized by spongiform degeneration, neuronal loss, PrPSc plaque formation, and gliosis in the central nervous system [1]. The autocatalytic conversion of the cellular prion protein (PrPC) into the pathologic isoform PrPSc is a key feature in prion propagation and prion disease pathogenesis. Prions propagate in the endocytic pathway of cells and endosomal and lysosomal compartments are involved in trafficking, re-cycling and final degradation of PrPSc [2,3]. In persistently prion-infected cells there is equilibrium between prion propagation and lysosomal clearance of prions. Shifting this equilibrium towards clearance reduces the cellular load of prions [4]. Consequently, chemical induction of the autophagic flux in cells is an example of how the cellular clearance of prions can be increased [5].

Macro-autophagy (here referred to as autophagy) is a basic cellular process for the degradation and recycling of organelles and cytoplasmic proteins, and nutrient supply under starvation [6]. Beyond these classical roles , autophagy contributes to various physiological processes such as intracellular cleansing, differentiation, longevity, elimination of invading pathogens, antigen transport to innate and adaptive immune systems, or counteracting endoplasmic reticulum stress [7**]. Moreover, autophagy is also directly implicated in patho-physiology and disease, interestingly both in promoting and protective functions. Autophagy plays a role in cancer, infectious and inflammatory diseases, and protein misfolding diseases [7**]. A role of autophagy in the pathogenesis of prion diseases was suggested early, e.g. by findings of autophagic vacuoles in the brains of CJD patients, tissues of experimentally prion-infected rodents, and in prion-infected cultured cells [8–11]. The concept was developed that small molecule enhancers of autophagy can be used for targeting neurodegenerative disorders [12], and work from various groups has provided experimental proof-of-concept for this [13*,14].

As the majority of PrPSc in persistently prion-infected cells resides within endocytic vesicles, access of autophagy to this PrPSc population is mostly of indirect nature [4, 5]. When autophagosomes fuse with late endosomes/multivesicular bodies (MVB) or lysosomes for final degradation of cargo in autophagolysosomes, PrPSc present in endosomal-lysosomal compartments can be subject to changes in the activity of autophagy [5]. Besides this involvement in lysosomal degradation of prions, we postulated that autophagy could be implicated in prion biogenesis and recycling [5]. Furthermore, we have recently showed that autophagic activity modulates exosomal release of prions [15**].

In this review we focus on the roles of autophagy in lysosomal clearance and exosomal release of prions, and how these can be exploited as therapeutic targets.

The interplay between autophagy, exosomes and prion disease

Autophagy is a highly conserved homeostatic process for isolation and degradation of misfolded proteins and damaged organelles upon fusion of autophagosomes with late endosomes or lysosomes[6]. Autophagosomes undergo a series of controlled maturation steps, before they fuse with lysosomes or with multivesicular bodies (MVBs) for lysosomal degradation of cargo [16,17]. MVBs are derived from endosomes by inward budding of their limiting membrane [18]. They are subjected to either fusion with the plasma membrane and secretion of intraluminal vesicles as exosomes or to maturation into lysosomes for degradation (Fig. 1). In addition, MVBs can fuse with autophagosomes to give rise to amphisomes [19], thereby linking the endosomal-lysosomal pathway with the autophagic machinery. The crosstalk between the endosomal and autophagosomal pathways has been addressed recently [20]. Upon autophagy stimulation by starvation or rapamycin treatment, MVBs are preferentially directed to the autophagic pathway for autophagic/lysosomal degradation, which results in reduced exosomal release [21]. In contrast, pharmacologic or genetic blocking of autophagy usually increases exosomal release [22], which can have implications in amyloid diseases. Indeed, blocking the autophagy/lysosomal pathway via silencing of ATG5 resulted in increased exosomal release of α-synuclein aggregates which are associated with Parkinson’s disease [23**].

Figure 1: Overview of PrPSc fates through endocytic/exosomal pathway and/or autophagic pathway.

Figure 1:

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PrPSc is synthesized at the plasma membrane and along the endocytic compartment. PrPSc is either returned to the cell membrane via recycling endosomes or goes to late endosomes/MVBs (blue arrows). Fusion of late endosomes with the plasma membrane results in the release of exosomes that contain PrPSc into the extracellular space (purple arrow). Macroautophagy starts with the nucleation step by forming an isolation membrane followed by expansion of phagophores, which engulf misfolded proteins and damaged organelles. Sealing of the double-membraned phagophore results in autophagosome formation, which subsequently fuses with lysosomes for degradation (green arrows). In lieu, autophagosomes can fuse with late endosomes/MVBs to form hybrid multivesicular organelles termed amphisomes, which are subsequently submitted to lysosomal degradation (black arrows). Since the vast majority of cellular PrPSc is contained within endosomal vesicles, access of autophagy is mostly indirect. Increase of autophagic flux results in more fusion events of autophagosomes with PrPSc-containing MVBs or lysosomes, resulting in less exosomal release and more lysosomal degradation.

In this context, prion-infected cell cultures are unique models to delineate the link between autophagy and the biogenesis and release of exosomes. Cell-to-cell transfer of prions, involving direct cell contact or cell-free mechanisms, plays a pivotal role in the spreading of prions through infected tissues [11,24*]. PrPSc is associated with exosomes, and stimulating exosomal release by treatment with the ionophore monensin increases the intercellular transfer of prions [25]. Exosomal prions were also detected in blood using immunochemistry technique [26]. Recently, we reported that exosomes isolated from prion-infected cultured mouse cells of central nervous system (ScCAD5) and peripheral nervous system origin (ScN2a) contain prions. Autophagy stimulation with rapamycin hindered the exosomal release of prions. Conversely, inhibition of autophagy by wortmannin treatment or CRISPR/Cas9-mediated knock-out of autophagy related protein-5 (Atg5) elevated the release of exosomes and exosome-associated prions. Our results demonstrate that autophagy modulation can control lateral transfer of prions by interfering with their exosomal release [15**].

It is important to note that the crosstalk between autophagy and exosomal release is context dependent. In rotenone-treated cancer stem cells the release of exosomes is accompanied by mitochondrial damage and increased autophagy. These data support the association between mitochondrial damage, autophagy induction, and the release of exosomes in certain disease scenarios [27]. In the context of neurodegenerative disorders, compromised autophagy or lysosomal function in neuronal cell lines increases the secretion of amyloid proteins in exosomes, which is believed to enhance the transfer of amyloid proteins to neighbouring cells [15**,28,29].

Of note, the malfunction of basal autophagy results in neurodegeneration. Mice deficient for Atg5 in neuronal cells develop progressive deficits in their motor function, accompanied by the accumulation of cytoplasmic inclusion bodies in neurons [30]. In prion infection, on the one hand siRNA-mediated knock-down of Atg5 in prion-infected cultured neuronal cells increases the level of PrPSc. This is explained by more lateral infection due to enhanced exosomal release of prions and less intracellular PrPSc clearance in lysosomes [15**, 31]. On the other hand, autophagy stimulation using chemical compounds reduces prion levels by facilitating their lysosomal clearance [32**–34, 35**].

Taken together, increasing evidence indicates that autophagy modulation plays a role in prion disease and is a promising therapeutic target for prion and prion-like diseases.

Pharmacological induction of autophagy reduces prions and mitigates prion disease

Various studies in vitro and in vivo showed that induction of autophagy interferes with prion infection (Table 1) [5,32**]. Several pharmacological inducers of autophagy were studied in persistently prion-infected cells or mice [33,36–38]. Some of these compounds induce autophagy through inhibition of mTOR, which negatively regulates autophagy [39]. Others work in mTOR-independent pathways.

Table 1. Therapeutic agents proven to alleviate prion infection via autophagy induction.

: decrease in PrPSc level; (−): completely clears PrPSc; i.p: intraperitoneally; i.c: intracerebrally; dpi: days post inoculation.

Therapeutic agent In vitro In vivo References
Imatinib mesylate, also known as Gleevec or STI571 ↓ RML- and 22L-N2a cells Injection of imatinib mesylate (i.p) for 30 days delayed neuro-invasion and prolonged survival of RML-infected mice. [33,40,41]
Lithium ↓ RML-N2a and 22L-L929 cells Oral lithium treatment started at 100 dpi in 139A i.c-infected mice did not prolong the survival significantly (some trend). [34]
Rapamycin ↓ RML-N2a cells and Fukuka-1 infected N2a cells. Oral rapamycin treatment started at 100 dpi prolonged survival of 139A i.c-infected mice.

Injection of rapamycin (i.p) 3 times per week, beginning at 6 weeks of age, prolonged survival of Tg(PrP-A116V) mice (GSS model).		 [31,34,38,42]
Trehalose ↓ RML-N2a cells. Trehalose in drinking water had no effect on the survival of 139A i.p-infected mice. However, it decreased PrPSc load in spleen after 30 and 60 dpi. [31]
FK506 (Tacrolimus) ↓ Fukuoka-1 -infected N2a58 cells and RML- and 22L-PK1 cells. Injection of FK506 (i.p) prolonged survival of Fukuoka-1 i.c-infected CD1 mice. [37,47]
Celecoxib derivatives (AR-12), also known as OSU-03012 ↓ 22L-N2a, 22L-CAD5, and 22L-, RML, and Me7-MEF cells

(−) on long term treatment (2 weeks)		 Injection of AR-12 (i.p) prolonged survival of RML i.c-infected mice (B. Abdulraham & KM. Schatzl, personal communication). [32]
Spermine ↓ SMB.sl5 and 22L-CAD5 cells. Not reported. [35]
Astemizole ↓ RML- and 22L-PK1 cells. Injection of astimizole (i.p.) for 30 days prolonged survival of RML i.c- infected mice, however it was not statistically significant (p=0.06). [47]
Resveratrol (−)SMB-S15 cells.

Blocked neurotoxicity induced by PrP peptide (106–126) – in SH-SY5Y and SK-K-SH cells.		 Oral resveratrol had no effect on survival of Me7 i.c-infected mice (J. Braun and H.M. Schatzl, personal communication). [36,44]
Ginsenoside-Rg3 Blocked neurotoxicity induced by PrP peptide (106–126) in primary neurons and SK-K-SH cells. Not reported. [45]
Hinokitiol Attenuated neurotoxicity induced by PrP peptide (106–126) in primary neurons and SK-K-SH cells. Not reported [46]
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The first compound for which induction of autophagy was described as underlying anti-prion mechanism is imatinib mesylate (Gleevec®, STI571), an inhibitor of the tyrosine kinase c-Abl. Initial studies found increased lysosomal clearance of PrPSc in cultured prion-infected cells when treated with low micromolar range concentrations of imatinib [33]. Follow-up studies revealed that imatinib dose-dependently activates the cellular autophagy machinery in mammalian cells, independent of their tissue type, species origin or immortalization status [40]. Time course studies of intraperitoneally (i.p) prion-infected mice showed that imatinib treatment for 30 days at an early phase of infection strongly reduced the PrPSc loads in the spleen and, to a lesser extent, in the spinal cord. It also delayed PrPSc accumulation in the brain and prolonged the survival time of treated mice (mean survival of treatment group was 263 days versus 246 days for the control) [41]. Imatinib does not efficiently cross the blood-brain-barrier and effects on prion infection were less pronounced when neuroinvasion was already accomplished [41].

Rapamycin, the classical mammalian target of rapamycin (mTOR) inhibitor and well recognized autophagy inducer, prolonged the survival of intracerebrally prion-infected mice (strain 139A) by averaging 13 days, when administered orally starting at 100 days p.i. [34]. In another study, rapamycin-treated Tg(PrP-A116V) mice, a model of Gerstmann-Sträussler-Scheinker syndrome (GSS), showed delayed disease onset and prolonged survival on average by 16 days compared to the vehicle treated controls [42]. Whereas imatinib mainly exerted its anti-prion effects outside the central nervous system, these two studies indicate a potential for rapamycin to cross the blood-brain-barrier and act within the brain. Interestingly, the anti-prion effect of rapamycin is strain-dependent in vitro. Rapamycin treatment reduced PrPSc in mouse neuroblastoma cells (ScN2a) persistently infected with the Fukuoka-1 strain but had no effect in ScN2a cells infected with 22L or Chandler/RML scrapie strains. This indicates a more efficient degradation of Fukuoka-1 prions by the autophagy pathway compared to other prion strains [38]. Other drugs induced autophagy and reduced PrPSc in prion-infected cells but were less efficient in in vivo experiments. Lithium chloride (LiCl) used to treat manic depressive illnesses and mood disorders, induces autophagy by mTOR-independent pathways. Despite having no statistically significant effect on the survival of 139A-infected mice, LiCl treatment cleared PrPSc in ScN2a cells after 10 days of treatment [34]. The non-reducing disaccharide trehalose reduced PrPSc in persistently prion-infected cultured cells [31]. It up-regulated autophagy markers in treated cells and its antiprion effect was inhibited by simultaneous application of autophagy inhibitors like 3-MA or silencing Atg5 expression using siRNA. Trehalose is another mTOR-independent autophagy inducer which was able to lower the PrPSc load in the spleen of intraperitoneally prion infected mice, however it did not prolong the survival significantly when applied orally [31].

A recent study published by our group demonstrated the potent anti-prion effect of AR-12, a celecoxib derivative also known as OSU-03012. AR-12 completely eradicated prion infection in persistently prion-infected neuronal (ScN2a) and non-neuronal (ScMEF) cultured cells after 2 weeks of treatment. No prion conversion activity was detectable by real-time quaking induced conversion (RT-QuIC), a highly sensitive in vitro prion amplification assay [32**]. Interestingly, intraperitoneal application of AR12 for 4 weeks to intracerebrally prion-infected FVB mice (scrapie prion strain RML) extended their survival on average by 11 days compared to that of the control group (manuscript in preparation), demonstrating that AR-12 has in vivo anti-prion effects. The effect of AR12 on PrPSc levels in vitro was less pronounced in ScN2a cells with Atg-5 knock-out, and the autophagy marker LC3-II was up-regulated in treated Atg5 wild-type cells. These findings indicate that induction of autophagy is an underlying mechanism for the observed anti-prion effects, although the exact mechanism by which AR-12 is inducing autophagy is not fully understood. Hitherto, AR-12 was shown to activate PERK, a key regulatory kinase for unfolded protein response in eukaryotic cells, which in turn phosphorylates eIF2α and induces the formation of the Atg5-Atg12 complex [43].

Recently, the natural polyamine spermine was found to clear PrPSc in prion-infected CAD5 and SMB.s15 cultured cells by induction of autophagy. Mass spectroscopy studies revealed that spermine induced hyperacetylation of tubulins, especially Tubb6, which in turn enhances the retrograde transport of autophagosomes to lysosomes [35**].

Resveratrol, a natural phenol and phytoalexin enriched in grapes, cured prion infection in SMB-s15 cells which was confirmed by inoculation of CD1 mice with resveratrol-treated cells [44]. In addition, resveratrol blocked the neurotoxicity caused by prion protein peptide (106–126) in cultured cells [36]. Oral application of resveratrol had no effect on survival or onset of prion disease in intracerebrally Me7-infected mice (J. Braun and H.M. Schatzl, personal communication). The anti-prion and neuroprotective effects of resveratrol were attributed to induction of autophagy through activation of Sirt1, a class III histone deacetylase [36]. Other natural compounds like hinokitiol and Ginsenoside-RG3, an active ingredient in ginseng, attenuated the neurotoxicity induced by prion protein peptide (106–126) in primary neurons and SK-K-SH cells through induction of autophagy [45,46]. Hinokitiol induced autophagy by stabilization of HIF-1α (Hypoxia inducible factor-1α), but the mechanism by which Ginsenoside-RG3 activates autophagy is to be determined [46]. There are no reports on whether these compounds have anti-prion effects in vitro or in vivo.

FK506 (tacrolimus), an immunosuppressant drug, decreased PrPSc in three different models of prion-infected neuroblastoma cells [37,47]. When administered intraperitoneally to prion-infected CD1 mice (strain Fukuoka-1), the mice survived 16 days longer than the controls [37]. FK506 treatment up-regulated autophagic markers in cell culture and in brain tissues of treated mice [37]. Like rapamycin, FK506 is a ligand of FK506 binding proteins (FKBPs), of which FKBP12 is the prototype. Although the rapamycin/FKBP12 complex inhibits mTOR, the FK506/FKBP12 complex interacts with the phosphatase calcineurin [48], and it needs to be determined whether activation of autophagy depends on inhibition of calcineurin [37].

In the high-throughput drug screening study which identified FK506, the antihistaminic astemizole was found to have anti-prion effects in vitro and in vivo [47]. In vitro, astemizole inhibited the replication of RML and 22L prions in neuroblastoma cells, without reappearance of the signal after treatment cessation. Additionally, the autophagy marker LC3II/I ratio was increased in astemizole-treated cells [47]. In vivo, the intraperitoneal injection of astemizole increased the survival of RML-infected mice by 6 days compared to that of the control [47].

Conclusion

Strong evidence suggests that autophagy plays a role in prion disease, with autophagosomes being observed in brains of patients and experimentally inoculated mice. However, this level of autophagy is not sufficient to resolve prion infection. Enhancing autophagy using chemical compounds has proven to increase PrPSc degradation, to limit its exosomal release, and to confer neuroprotection. While these multiple ways to interfere with prion propagation through autophagy are highly efficient in vitro, only a limited number of compounds also were efficient in extending the survival of prion-infected mice, calling for new approaches to strengthen these findings. A possible way to improve the encouraging in vivo anti-prion effects can be treatment with a combination of drugs. For example, a combination treatment with inducers of autophagy and compounds that inhibit de novo prion conversion can result in additive or even synergistic anti-prion effects. Some of the most promising drugs in vitro, such as imatinib, only poorly penetrate the blood brain barrier. Therefore, another strategy can be to pharmacologically improve existing drugs in order to facilitate efficient delivery into the brain. Nevertheless, extensive research is necessary to gain a full mechanistic understanding of the role of autophagy in prion infection in order to move those promising approaches from bench to bedside.

Highlights:

  • Prions are misfolded proteins causing fatal neurodegenerative diseases

  • Autophagy dictates the fate of PrPSc in various contexts in prion infection

  • Autophagy facilitates delivery of prions to lysosomal degradation

  • Increase in autophagy reduces the exosomal release of prion infectivity

  • Pharmacological stimulation of autophagy is beneficial in prion infection.

Achnowledgement

This work was supported by grants from Alberta Innovates/Alberta Prion Research Institute (APRI) (201300020), the National Institute of Health (R01 NS076853-01A1), and was performed within the framework of the Calgary Prion Research Unit (APRI grant 201600010). SG is supported by the Canada Research Chairs program.

Footnotes

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