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Published on: November 19, 2010
Decrease of RyR2 in the prion infected cell line and in the brains of the scrapie infected mice models and the
Qi Shi1, Jian-Le Li1,2, Yue Ma1
1a State Key Laboratory for Infectious Disease Prevention and Control , Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention , Beijing , People's Republic of China.
Abstract:
The levels of ryanodine receptors (RyRs) are usually increased in the brains of human Alzheimer disease (AD) and AD animal models. To evaluate the underlying alteration of brain RyRs in prion disease, scrapie infected cell line SMB-S15 and its infected mice were tested. RyR2 specific Western blots revealed markedly decreased RyR2 levels both in the cells and in the brains of infected mice. Assays of the brain samples of other scrapie (agents 139A and ME7) infected mice collected at different time-points during incubation period showed time-dependent decreases of RyR2. Immunofluorescent assays (IFA) verified that the expression of RyR2 locates predominantly in cytoplasm of SMB cells and overlapped with the neurons in the brain slices of mice. Furthermore, significant down-regulation of RyR2 was also detected in the postmortem cortical brains of the patients of various types of human prion diseases, including sporadic Creutzfeldt-Jakob disease (sCJD), fatal familial insomnia (FFI) and G114V-genetic CJD. Our data here propose the evidences of remarkably decreased brain RyR2 at terminal stages of both human prion diseases and prion infected rodent models. It also highlights that the therapeutic strategy with antagonist of RyRs in AD may not be suitable for prion disease.
Insights
Prion diseases, unlike Alzheimer's, show decreased brain ryanodine receptors (RyRs). This study found lower RyR2 levels in prion-infected cells, mice, and human prion disease brains, suggesting different therapeutic approaches are needed.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Ryanodine receptors (RyRs) are implicated in Alzheimer's disease (AD) pathogenesis, with typically elevated brain levels.
- Prion diseases are neurodegenerative disorders caused by misfolded prion proteins, distinct from AD.
- Understanding alterations in brain proteins like RyRs is crucial for differentiating and treating neurodegenerative conditions.
Purpose of the Study:
- To investigate the expression levels and localization of ryanodine receptors (RyRs) in prion disease models and human prion diseases.
- To compare the changes in RyR levels in prion disease with those observed in Alzheimer's disease.
- To assess the potential therapeutic implications of RyR alterations in prion diseases.
Main Methods:
- Western blot analysis to quantify RyR2 levels in scrapie-infected SMB-S15 cells and prion-infected mouse brains.
- Immunofluorescent assays (IFA) to determine the cellular localization of RyR2 in cells and brain slices.
- Analysis of postmortem brain samples from patients with sporadic Creutzfeldt-Jakob disease (sCJD), fatal familial insomnia (FFI), and G114V-genetic CJD.
Main Results:
- Markedly decreased RyR2 levels were observed in SMB-S15 cells infected with scrapie and in the brains of infected mice.
- A time-dependent decrease in RyR2 levels was noted in mice infected with different scrapie agents (139A and ME7).
- Significant down-regulation of RyR2 was confirmed in postmortem cortical brain samples from patients with sCJD, FFI, and G114V-genetic CJD.
Conclusions:
- Prion diseases are characterized by a significant decrease in brain ryanodine receptor 2 (RyR2) levels, contrasting with Alzheimer's disease.
- RyR2 down-regulation occurs in both animal models and human cases of prion disease.
- Therapeutic strategies targeting RyRs, such as antagonists used in AD, may not be suitable for prion diseases due to these opposing alterations.
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