Antigenic mimicry-mediated anti-prion effects induced by bacterial enzyme succinylarginine dihydrolase in mice

Ishibashi, Daisuke; Yamanaka, Hitoki; Mori, Tsuyoshi; Yamaguchi, Naohiro; Yamaguchi, Yoshitaka; Nishida, Naoshi; Sakaguchi, Suehiro

doi:10.1016/j.vaccine.2011.10.017

Cited by 16 publications

(13 citation statements)

References 24 publications

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“…ScN2a58 cells originated from N2a58 cells infected with a mouse-adapted scrapie strain, 22 L, as previously described 36 37 38 . FK-N2a58 cells originated from N2a58 cells infected with a mouse-adapted Gerstmann-Sträussler-Scheinker (GSS) strain, Fukuoka-1, as previously described 39 . HpL2-3 cells are immortalized hippocampal cells derived from PrP-deficient mice, a kind gift from Prof. Takashi Onodera (The University of Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

Ubiquitin-specific protease 14 modulates degradation of cellular prion protein

Homma

Ishibashi

Nakagaki

et al. 2015

Sci Rep

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Prion diseases are fatal neurodegenerative disorders characterized by the accumulation of prion protein (PrPC). To date, there is no effective treatment for the disease. The accumulated PrP, termed PrPSc, forms amyloid fibrils and could be infectious. It has been suggested that PrPSc is abnormally folded and resistant to proteolytic degradation, and also inhibits proteasomal functions in infected cells, thereby inducing neuronal death. Recent work indicates that the ubiquitin-proteasome system is involved in quality control of PrPC. To reveal the significance of prion protein ubiqitination, we focused on ubiquitin-specific protease 14 (USP14), a deubiqutinating enzyme that catalyzes trimming of polyubiquitin chains and plays a role in regulation of proteasomal processes. Results from the present study showed that treatment with a selective inhibitor of USP14 reduced PrPC, as well as PrPSc, levels in prion-infected neuronal cells. Overexpression of the dominant negative mutant form of USP14 reduced PrPSc, whereas wildtype USP14 increased PrPSc in prion-infected cells. These results suggest that USP14 prevents degradation of both normal and abnormal PrP. Collectively, a better understanding about the regulation of PrPSc clearance caused by USP14 might contribute greatly to the development of therapeutic strategies for prion diseases.

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Section: Methodsmentioning

confidence: 99%

Ubiquitin-specific protease 14 modulates degradation of cellular prion protein

Homma

Ishibashi

Nakagaki

et al. 2015

Sci Rep

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“…1,2 For this reason, drug discovery for the prion diseases has focused primarily on compounds capable of inhibiting the conversion of PRNP. A number of drugs, including pentosan polysulfate (PPS), 3 quinacrine, 4 anti-PRNP antibodies 5,6 and others, 7,8 have been proposed as potential anti-prion agents. Most act by binding to PRNP C and inhibiting the interaction between PRNP C and PRNP Sc , resulting in a reduction of the conversion of PRNP C into PRNP Sc .…”

Section: Introductionmentioning

confidence: 99%

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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“…Moreover, Ishibashi et al discovered that the bacterial succinylarginine dihydrolase (SADH) contained an amino acid sequence similar to the epitope recognized by the 6H4 anti-PrP monoclonal antibody. Using recombinant SADH as an immunogen, they showed that this strategy is able to extend the survival of prion-infected mice [76].…”

Section: Active Immunization Against Prion Diseasesmentioning

confidence: 99%

Immunotherapy against Prion Disease

2020

Pathogens

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The term “prion disease” encompasses a group of neurodegenerative diseases affecting both humans and animals. Currently, there is no effective therapy and all forms of prion disease are invariably fatal. Because of (a) the outbreak of bovine spongiform encephalopathy in cattle and variant Creutzfeldt–Jakob disease in humans; (b) the heated debate about the prion hypothesis; and (c) the availability of a natural prion disease in rodents, the understanding of the pathogenic process in prion disease is much more advanced compared to that of other neurodegenerative disorders, which inspired many attempts to develop therapeutic strategies against these fatal diseases. In this review, we focus on immunotherapy against prion disease. We explain our rationale for immunotherapy as a plausible therapeutic choice, review previous trials using either active or passive immunization, and discuss potential strategies for overcoming the hurdles in developing a successful immunotherapy. We propose that immunotherapy is a plausible and practical therapeutic strategy and advocate more studies in this area to develop effective measures to control and treat these devastating disorders.

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Antigenic mimicry-mediated anti-prion effects induced by bacterial enzyme succinylarginine dihydrolase in mice

Abstract: Prions, the causative agents of prion diseases, are immunologically tolerated because their major component, prion protein (PrP), is a host-encoded molecule. Therefore, no effective prion vaccines have been developed. We previously showed that heterologous bovine and 3

Cited by 16 publications

References 24 publications

Ubiquitin-specific protease 14 modulates degradation of cellular prion protein

Ubiquitin-specific protease 14 modulates degradation of cellular prion protein

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

Immunotherapy against Prion Disease

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