The aggravating role of the ubiquitin-proteasome system in neurodegenerative disease.
Intraneuronal inclusion bodies are key pathological features of most age-related neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. These inclusions are commonly characterized both by the presence of ubiquitinated proteins and the sequestration of components of the UPS (ubiquitin-proteasome system). Unfortunately, as we age, the efficiency of the UPS declines, suggesting that the presence of ubiquitinated proteins and UPS components in inclusions may reflect unsuccessful attempts by the (failing) UPS to remove the aggregating proteins. Whether the physical presence of inclusions causes cell death or, conversely, whether they are non-toxic and their presence reflects a cellular protective mechanism remains highly controversial. Animal and in vitro model systems that allow detailed characterization of the inclusions and their effects on the cell have been developed by us and others. Identification of the mechanisms involved in inclusion formation is already aiding the development of novel therapeutic strategies to prevent or alleviate aggregate-associated neurodegenerative diseases.
Hung
C-C
CC
Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
Davison
E J
EJ
Robinson
P A
PA
Ardley
H C
HC
D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism
D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex