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The cellular mechanisms behind prion biosynthesis and metabolism remain unclear. Here we show that secretin signaling via the secretin receptor regulates abnormal prion protein formation in prion-infected cells. Animal studies demonstrate that secretin receptor deficiency slightly, but significantly, prolongs incubation time in female but not male mice. This gender-specificity is consistent with our finding that prion-infected cells are derived from females. Therefore, our results provide initial insights into the reasons why age of disease onset in certain prion diseases is reported to occur slightly earlier in females than males., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Protein-bound polysaccharide K (PSK) is a clinical immunotherapeutic agent that exhibits various biological activities, including anti-tumor and anti-microbial effects. In the present study, we report on the anti-prion activity of PSK. It inhibited the formation of protease-resistant abnormal prion protein in prion-infected cells without any apparent alterations in either the normal prion protein turnover or the autophagic function in the cells. Its anti-prion activity was predominantly composed of the high molecular weight component(s) of the protein portion of PSK. A single subcutaneous dose of PSK slightly but significantly prolonged the survival time of peritoneally prion-infected mice, but PSK-treated mice produced neutralizing antibodies against the anti-prion activity of PSK. These findings suggest that PSK is a new anti-prion substance that may be useful in elucidating the mechanism of prion replication, although the structure of the anti-prion component(s) of PSK requires further evaluation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Gamma-aminobutyric acid type A (GABAA) receptor beta1 (gabrb1), a subunit of GABAA receptors involved in inhibitory effects on neurotransmission, was found to associate with the formation of protease-resistant prion protein in prion-infected neuroblastoma cells. Silencing of gabrb1 gene expression significantly decreased the abnormal prion protein level but paradoxically increased the normal prion protein level. Treatment with a gabrb1-specific inhibitor, salicylidene salicylhydrazide, dose-dependently decreased the abnormal prion protein level, but silencing of other GABAA receptor subunits' gene expression and treatments with the receptor antagonists and agonists did not. Therefore, gabrb1 involvement in abnormal prion protein formation is independent of GABAA receptors., (Copyright 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Recent outbreaks of variant Creutzfeldt-Jakob disease and iatrogenic Creutzfeldt-Jakob disease have aroused great concern in many countries and have necessitated the development of suitable therapies. We have demonstrated that sulfated glycans such as pentosan polysulfate and fucoidan, and amyloidophilic compounds such as amyloid dye derivatives, styrylbenzoazole derivatives, and phenylhydrazine derivatives have efficacies in prion-infected animals. Amyloidophilic compounds present potentialities not only as therapeutic candidates but also as prion amyloid imaging probes for use in nuclear medicine technology such as positron emission tomography. A representative of styrylbenzoazole compounds has been used recently for clinical trials of brain prion amyloid imaging in patients. On the other hand, a representative of phenylhydrazine compounds, compB, displays excellent effectiveness in prolonging the incubation times of infected animals when given orally. However, both its anti-prion effectiveness in vitro and its therapeutic efficacy in vivo are consistently dependent on the prion strain. This prion-strain-dependency is similarly observed in other amyloidophilic compounds. Therefore, aside from further improvement of the safety profiles and pharmacokinetic properties of such compounds, elucidation and management in the mechanism of the prion strain-dependent effectiveness is necessary. Nevertheless, because compB studies suggest that amyloidophilic compounds are also therapeutic candidates for Alzheimer's disease, amyloidophilic compounds might be attractive as drug candidates for various conformational diseases and hasten development of therapeutic drugs for prion diseases.

Abstract: γ-Aminobutyric acid type A (GABAA) receptor β1 (gabrb1), a subunit of GABAA receptors involved in inhibitory effects on neurotransmission, was found to associate with the formation of protease-resistant prion protein in prion-infected neuroblastoma cells. Silencing of gabrb1 gene expression significantly decreased the abnormal prion protein level but paradoxically increased the normal prion protein level. Treatment with a gabrb1-specific inhibitor, salicylidene salicylhydrazide, dose-dependently decreased the abnormal prion protein level, but silencing of other GABAA receptor subunits’ gene expression and treatments with the receptor antagonists and agonists did not. Therefore, gabrb1 involvement in abnormal prion protein formation is independent of GABAA receptors. [Copyright &y& Elsevier]