Cytosolic Prion Protein Toxicity Is Independent of Cellular Prion Protein Expression and Prion Propagation

Norstrom, Eric M.; Ciaccio, Mark F.; Rassbach, Benjamin; Wollmann, Robert; Mastrianni, James A.

doi:10.1128/jvi.02157-06

Cited by 18 publications

(20 citation statements)

References 35 publications

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“…143 However, neither brain tissue from these mice, nor cells overexpressing cyPrP were transmissible to normal mice, suggesting a toxic but not infectious property. 144 Cytosolic PrP has not been demonstrated in human PrD, but electron microscopy studies have identified low levels of free PrP in the cytosolic compartment. 171 Several lines of evidence suggest that PrP Sc transmission and toxicity depend on the presence of PrP C on the plasma membrane.…”

Section: Prion Pathogenesismentioning

confidence: 97%

“…143 Because mice that express only cytosolic PrP are resistant to prion infection, this fraction of PrP may function principally as a toxic, rather than infectious, component, as these mice were found to be resistant to prion inoculation. 144 Propagation of PrP Sc occurs by a process that may be quite distinct from initiation. In this case, an infectious unit of PrP Sc has already been generated by one of the three mechanisms discussed earlier.…”

Section: Figure 215 Initiation and Propagation Of Scrapie-associatedmentioning

confidence: 99%

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Prion Diseases

Mastrianni

2015

Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease

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Section: Prion Pathogenesismentioning

confidence: 97%

Section: Figure 215 Initiation and Propagation Of Scrapie-associatedmentioning

confidence: 99%

Prion Diseases

Mastrianni

2015

Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease

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“…At least one of these forms is associated with some familial forms of neurodegeneration caused by PRNP mutations [36]. Importantly, neither cyPrP nor Ctm PrP is transmissible [36,44]. They apparently elicit their effects by causing some type of proteinopathy, in which increased levels of an aberrant form of a normal protein cause cellular dysfunction (by downstream mechanisms that remain to be elucidated).…”

Section: Deviation From Normal Levels Of Prp Forms Can Cause Neurodegmentioning

confidence: 99%

Prion protein biosynthesis and its emerging role in neurodegeneration

Chakrabarti

Ashok

Hegde

2009

Trends in Biochemical Sciences

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Various fatal neurodegenerative disorders are caused by altered metabolism of the prion protein (PrP). These diseases are typically transmissible by an unusual ‘protein-only’ mechanism in which a misfolded isomer, PrPSc, confers its aberrant conformation onto normal cellular PrP. An impressive range of studies has investigated nearly every aspect of this fascinating event; yet, our understanding of how PrPSc accumulation might lead to cellular dysfunction and neurodegeneration is trifling. Recent advances in our understanding of normal PrP biosynthesis and degradation might have unexpectedly shed new light on this complex problem. Indeed, our current understanding of normal PrP cell biology, coupled with a growing appreciation of its complex metabolism, is providing new hypotheses for PrP-mediated neurodegeneration.

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“…Therefore, it is possible that the efficiency of the ubiquitin-proteasomal system will decrease along with aging, leading the aged neurons more vulnerable to the accumulation of misfolded proteins. However, some studies have also revealed that accumulation of PrP in cytosol is not toxic for neurocytes and the CytoPrP is inaccessible to PrP Sc in transgenic mice (6,16), which may indicate a more complicated mechanism. Further analysis of the cellular proteasomal status during TSE will help to address the role of proteasomal impairment in the pathogenesis of TSE.…”

Section: Accumulation Of Cytoprp In Cytoplasm Leads To Reduction Of Bmentioning

confidence: 99%