Document Detail

Misfolded PrP and a novel mechanism of proteasome inhibition.
MedLine Citation:
PMID:  22453175     Owner:  NLM     Status:  MEDLINE    
Prion diseases comprise a family of fatal neurodegenerative disorders caused by the conformational re-arrangement of a normal host-encoded protein, PrP (C) , to an abnormal infectious isoform termed PrP (Sc) . Currently, the precise cellular mechanism(s) underlying prion disease pathogenesis remain unclear. Evidence suggests a role for the ubiquitin proteasome system (UPS), a protein degradation pathway that is critical for maintaining cellular proteostasis. Dysfunction of the UPS has been implicated in various neurodegenerative diseases. However, the mechanisms of this impairment remain unknown in many cases, and evidence that disease-associated misfolded proteins are able to directly inhibit the function of the proteasome has been lacking. Recently, we have shown data describing a mechanism of proteasome impairment by the direct interaction of β-sheet-rich PrP to reduce gate opening and inhibit substrate entry. This novel mechanism may provide a model for how other misfolded, disease-associated proteins might interact with the proteasome to disrupt its function. Targeting the UPS to restore proteostasis in neurodegenerative disorders in which misfolded proteins accumulate offers a possible target for therapeutic intervention.
Ralph Andre; Sarah J Tabrizi
Related Documents :
17217465 - The arabidopsis psbo2 protein regulates dephosphorylation and turnover of the photosyst...
21370075 - Data processing and analysis for protein microarrays.
21339145 - Foaming and emulsifying properties of porcine red cell protein concentrate.
19037505 - Towards building artificial light harvesting complexes: enhanced singlet-singlet energy...
25233445 - Serum differential proteomic analysis of endometriosis and adenomyosis by itraq technique.
10950865 - Multiple rgs proteins alter neural g protein signaling to allow c. elegans to rapidly c...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Prion     Volume:  6     ISSN:  1933-690X     ISO Abbreviation:  Prion     Publication Date:    2012 Jan-Mar
Date Detail:
Created Date:  2012-03-28     Completed Date:  2012-08-10     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  101472305     Medline TA:  Prion     Country:  United States    
Other Details:
Languages:  eng     Pagination:  32-6     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Models, Molecular
Prion Diseases / metabolism
Prions / chemistry*,  metabolism*
Proteasome Endopeptidase Complex / chemistry,  metabolism
Proteasome Inhibitors*
Protein Folding*
Ubiquitin / metabolism
Grant Support
G0700877//Medical Research Council; //Department of Health; //Medical Research Council
Reg. No./Substance:
0/Prions; 0/Proteasome Inhibitors; 0/Ubiquitin; EC Endopeptidase Complex

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Insights into the disparate action of osmolytes and macromolecular crowders on amyloid formation.
Next Document:  Early structural features in mammalian prion conformation conversion.