Autophagy induction by trehalose counter-acts cellular prion-infection

Aguib, Yasmine; Heiseke, Andreas; Gilch, Sabine; Riemer, Constanze; Baier, Michael; Schätzl, Hermann; Ertmer, Alexa

doi:10.4161/auto.5.3.7662

Cited by 204 publications

(167 citation statements)

References 44 publications

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“…Alternatively, our data showing elevated LC3II/I ratios are compatible with induction of autophagy and rapid degradation of TPrP. Although, obviously, TPrP and PrP Sc are different entities, it is noteworthy that PrP Sc degradation is accelerated by autophagy activation (65,66). Further studies aiming at understanding the differences between NTPrP and TPrP cellular processing will shed light on the cellular mechanisms of TPrP-induced neurotoxicity.…”

Section: Discussionmentioning

confidence: 58%

Highly neurotoxic monomeric α-helical prion protein

Zhou

Ottenberg

Sferrazza

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Prion diseases are infectious and belong to the group of protein misfolding neurodegenerative diseases. In these diseases, neuronal dysfunction and death are caused by the neuronal toxicity of a particular misfolded form of their cognate protein. The ability to specifically target the toxic protein conformer or the neuronal death pathway would provide powerful therapeutic approaches to these diseases. The neurotoxic forms of the prion protein (PrP) have yet to be defined but there is evidence suggesting that at least some of them differ from infectious PrP (PrP Sc ). Herein, without making an assumption about size or conformation, we searched for toxic forms of recombinant PrP after dilution refolding, size fractionation, and systematic biological testing of all fractions. We found that the PrP species most neurotoxic in vitro and in vivo (toxic PrP, TPrP) is a monomeric, highly α-helical form of PrP. TPrP caused autophagy, apoptosis, and a molecular signature remarkably similar to that observed in the brains of prion-infected animals. Interestingly, highly α-helical intermediates have been described for other amyloidogenic proteins but their biological significance remains to be established. We provide unique experimental evidence that a monomeric α-helical form of an amyloidogenic protein represents a cytotoxic species. Although toxic PrP has yet to be purified from prion-infected brains, TPrP might be the equivalent of one highly neurotoxic PrP species generated during prion replication. Because TPrP is a misfolded, highly neurotoxic form of PrP reproducing several features of prion-induced neuronal death, it constitutes a useful model to study PrP-induced neurodegenerative mechanisms.

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Section: Discussionmentioning

confidence: 58%

Highly neurotoxic monomeric α-helical prion protein

Zhou

Ottenberg

Sferrazza

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The importance of autophagy in the clearance of PRNP Sc is also supported by the fact that certain chemicals such as trehalose, 17 lithium 18 and rapamycin 19 decrease the amount of PRNP Sc in prion-infected cultured cells or mice by inducing the upregulation of autophagy. In contrast, treatment with trehalose or lithium did not significantly prolong the survival of prion-infected mice, although these findings may be partially explained by the fact that the effective concentration of both drugs is extremely high (mM range), and therefore difficult to achieve in vivo.…”

Section: Discussionmentioning

confidence: 91%

“…In contrast, treatment with trehalose or lithium did not significantly prolong the survival of prion-infected mice, although these findings may be partially explained by the fact that the effective concentration of both drugs is extremely high (mM range), and therefore difficult to achieve in vivo. 17,18 Rapamycin did extend survival to a moderate extent only under certain experimental conditions. 19,25 In our study, the early administration at 20 d.p.i of FK506 prolonged the survival of Fukuoka-1-infected mice.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 Of note, the chemical-induced enhancement of autophagy has been reported to decrease aggregates in the CNS and retard the progression of neurological symptoms in several animal and cell culture models of neurodegenerative diseases, including TSE. [14][15][16][17][18][19] The autophagy-lysosomal system is regulated by several mechanisms, one example of which is mechanistic target of rapamycin (MTOR) signaling. 20 FK506, also named tacrolimus, is well known as an immunosuppressive drug that is mainly used post-transplantation to decrease the activity of the recipient's immunity.…”

Section: Introductionmentioning

confidence: 99%

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FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

et al. 2013

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Prion diseases are fatal neurodegenerative disorders and no effective treatment has been established to date. in this study, we evaluated the effect of FK506 (tacrolimus), a macrolide that is known to be a mild immunosuppressant, on prion infection, using cell culture and animal models. We found that FK506 markedly reduced the abnormal form of prion protein (PRNP Sc ) in the cell cultures (N2a58 and MG20) infected with Fukuoka-1 prion. The levels of autophagy-related molecules such as Lc3-ii, ATG12-ATG5 and ATG7 were significantly increased in the FK506-treated cells, and resulted in the increased formation of autolysosomes. Upregulation of the autophagy-related molecules was also seen in the brains of FK506-treated mice and the accumulation of PRNP Sc was delayed. The survival periods in mice inoculated with Fukuoka-1 were significantly increased when FK506 was administered from day 20 post-inoculation. These findings provide evidence that FK506 could constitute a novel antiprion drug, capable of enhancing the degradation of PRNP Sc in addition to attenuation of microgliosis and neuroprotection.

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“…Trehalose-induced autophagy enhanced the clearance of autophagy substrates such as mutant huntingtin and A30P and A53T α-synuclein [43] . Furthermore, as a natural hemolymph sugar of invertebrates, trehalose may be a safe strategy for the treatment of two other neurodegenerative diseases, AD [44] and prion disease [45] . Notably, trehalose pre-treatment protected against pro-apoptotic insults by reducing mitochondrial load in addition to its autophagic induction role [43,46] .…”

Section: Small Molecule Enhancers Of Rapamycinmentioning

confidence: 99%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

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Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

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Autophagy induction by trehalose counter-acts cellular prion-infection

Cited by 204 publications

References 44 publications

Highly neurotoxic monomeric α-helical prion protein

Highly neurotoxic monomeric α-helical prion protein

FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

Application and interpretation of current autophagy inhibitors and activators

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