Prion diseases: Infectivity versus toxicity

Nature (Impact Factor: 41.46). 02/2011; 470(7335):470-1. DOI: 10.1038/470470a
Source: PubMed


Prions are infectious proteins that can cause deadly diseases in
mammals. Detailed measurements of infectivity suggest that there may be
distinct infectious and toxic versions of this protein. See Letter p.540

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    • "Transmissible spongiform encephalopathies or prion diseases are a family of progressive disorders caused by aggregating the scrapie isoform of the prion protein (PrPsc), which accumulates to form central nervous system plaque (Wickner, 2011). Mitochondrial failure caused by aggregation of misfolded proteins is a key mechanism of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and prion disease (Borger et al., 2011; Coskun et al., 2012; Sisková et al., 2010). "
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    ABSTRACT: Sirtuin 1 (Sirt1) is a class III histone deacetylase that mediates the protective effects of neurons in neurodegenerative disorders, including Alzheimer's and prion disease. However, the mechanism directly involved in neuroprotection is still poorly understood. Recent evidence has demonstrated that activating Sirt1 induces autophagy, and that activating autophagy protects neurons against neurodegenerative disorders by regulating mitochondrial homeostasis. Thus, we focused on the mechanism of the Sirt1-mediated neuroprotective effect that was associated with regulating mitochondrial homeostasis via autophagy. Adenoviral-mediated Sirt1 overexpression prevented prion protein (PrP)(106-126)-induced neurotoxicity via autophagy processing. Moreover, Sirt1-induced autophagy protected against the PrP(106-126)-mediated decrease in the mitochondrial membrane potential value. Additionally, Sirt1 overexpression decreased PrP(106-126)-induced Bax translocation to the mitochondria and cytochrome c release into the cytosol. Sirt1 knockdown using small interfering (si) RNAs induced downregulation of Sirt1 protein expression and sensitized neuron cells to PrP(106-126)-induced cell death and mitochondrial dysfunction. Knockdown of autophagy-related 5 (ATG5) using small interfering RNA decreased autophagy-related 5 and autophagy marker microtubule-associated protein 1 light chain 3-II protein levels and blocked the effect of a Sirt1 activator against PrP(106-126)-induced mitochondrial dysfunction and neurotoxicity. Taken together, this study is the first report demonstrating that autophagy induced by Sirt1 activation plays a pivotal role protecting against prion-induced neuron cell death and also suggests that regulating autophagy including which by Sirt1 activation may be a therapeutic target for neurodegenerative disorders including the prion disease.
    Neurobiology of aging 05/2012; 34(1). DOI:10.1016/j.neurobiolaging.2012.04.002 · 5.01 Impact Factor
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    ABSTRACT: Protein misfolding and assembly into ordered, self-templating aggregates (amyloid) has emerged as a novel mechanism for regulating protein function. For a subclass of amyloidogenic proteins known as prions, this process induces transmissible changes in normal cellular physiology, ranging from neurodegenerative disease in animals and humans to new traits in fungi. The severity and stability of these altered phenotypic states can be attenuated by the conformation or amino-acid sequence of the prion, but in most of these cases, the protein retains the ability to form amyloid in vitro. Thus, our ability to link amyloid formation in vitro with its biological consequences in vivo remains a challenge. In two recent studies, we have begun to address this disconnect by assessing the effects of the cellular environment on traits associated with the misfolding of the yeast prion Sup35. Remarkably, the effects of quality control pathways and of limitations on protein transfer in vivo amplify the effects of even slight differences in the efficiency of Sup35 misfolding, leading to dramatic changes in the associated phenotype. Together, our studies suggest that the interplay between protein misfolding pathways and their cellular context is a crucial contributor to prion biology.
    Prion 04/2011; 5(2):76-83. DOI:10.4161/pri.5.2.16413 · 2.24 Impact Factor
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    ABSTRACT: Our previous study demonstrated that hypoxia-inducible factor-1 (HIF-1)-mediated neuroprotective effects are related to cellular prion protein (PrPc) gene (PRNP) regulation under hypoxic conditions. However, the mechanism of HIF-1α-mediated PRNP gene regulation in prion-mediated neurodegenerative disorders is not clear. Transcription factor specific protein 1 (SP1) is necessary for PRNP transcription initiation, and SP1 gene expression is regulated through HIF-1α activation under hypoxic conditions. Thus, we hypothesized that HIF-1α-mediated neuroprotection is related to the SP1 transcription pathway as a result of PRNP gene regulation. Inhibition of SP1 expression blocked the HIF-1α-mediated protective effect against prion-mediated neurotoxicity. Also, knockdown of HIF-1α induced downregulation of SP1 expression and sensitivity to prion-mediated neurotoxicity, whereas upregulation of SP1 transcriptional activity lead to protection against prion-mediated neuron cell death and PRNP gene expression even in HIF-1α depleted cells. This report is the first study demonstrating that HIF-1α-mediated SP1 expression regulates PrPc transcription, and upregulation of SP1 induced by HIF-1α plays a key role in protection from prion-mediated neurotoxicity. These studies suggest that transcription factor SP1 may be involved in the pathogenesis of prion diseases and also may be a potential therapeutic option for neurodegeneration caused by the pathological prion protein, PrPsc.
    Biochemical and Biophysical Research Communications 11/2012; 429(1-2). DOI:10.1016/j.bbrc.2012.10.086 · 2.30 Impact Factor
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