Ubiquitin-proteasome system

Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system may be part of the pathophysiology of sporadic Parkinson s disease, especially... 

Protein modification by the covalent attachment of ubiquitin chains serves as a signal to mark proteins for the degradation by a multicatalytic proteinase complex called the proteasome. Thus the ubiquitin proteasome system (UPS) controls the stability of proteins in a... 

Ubiquitin is a highly conserved 8.5 kDa polypeptide, which was first described in 1974. The discovery that the Ubiquitin proteasome system serves as a general mechanism to target proteins for destruction by the proteasome was awarded with the Nobel Prize for Chemistry in 2004. 

In concordance with the central role of ubiquitin modification in multiple cellular functions perturbations of this system are associated with a variety of diseases. Defects in the control of cell cycle regulators by the ubiquitin proteasome system are connected to cancer progression and many E3 ligases were originally identified as oncogenes. 

McNaught, K. S., Olanow, C. W., Halliwell, B. et al. Failure of the ubiquitin-proteasome system in Parkinson s disease. Nature Reviews, Neuroscience 2 589-594, 2001. 

Oren, M., Schwartz, A. L. and Ciechanover, A. Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system ... 

Landon, M., Jamieson, C., ramage, R., Mayer, R. J., and Layfield, R. Inhibition of the ubiquitin-proteasome system in Alzheimer s disease. Proc. Nail. Acad. Sci. USA 2000, 97, 9902-06. 

Ciechanover, A. and Brundin, P. The ubiquitin proteasome system in neurodegenerative diseases sometimes the chicken, sometimes the egg. Neuron, 2003, 40, 427 6. 

How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol 2003, 4, 192-201. 

Glickman, M. H. and Ciechanover, A. The ubiquitin-proteasome system destruction for the sake of construction. Physiol. Rev. 2002, 82, 373-428. 

Alterations in APP processing associated with dysfunctions in the ubiquitin-proteasome system may be responsible in part for ABP accumulation (12). The protein deposits in NFTs, nenritic plaqnes, and nenropil threads in AD cortex contain forms of APP and nbiqnitin-B that are aberrant in the C-terminns (135-137). 

Increasing evidence indicates that accumulation of aberrant or misfolded proteins, protofibril formation, ubiquitin-proteasome system dysfunction, and the direct or indirect consequences of abnormal protein aggregation and accumulation represent deleterious events linked to neurodegeneration (255,256). Ubiquitination is an essential cellular process affected by a multienzyme cascade involving Els (ubiquitin-activating enzymes), E2s (ubiquitin-conjugation enzymes or UBCs), and E3s (ubiquitin-protein Ugases) (12,257) (see Fig. 10.4). 

An example that alterations in the ubiquitin-proteasome system may be a primary event in AD, after ABP-induced toxicity or accumulation, was provided by Konishi et al. (273), who found that frameshift ubiquitin-B was present in subjects with AD pathology prior to development of dementia, probably accumulating in the initial steps of AD pathogenesis, whereas complement proteins were detected in AD patients but not in subjects with AD pathology and no symptoms of dementia, indicating the involvement of complement proteins in the later stage of dementia (273). 

Ubiquitin interacts avidly but not covalently with ABP and such complexes can be isolated from AD brain extracts (276). Ubiquitin and APP colocalize to endosome-lysosomes implicated in APP proteolysis (277). A clear link between defective APP processing and the ubiquitin-proteasome system was demonstrated by Chen et al. 

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