Aggresome (green) forming next to DNA (blue).
Kopito/RUP
Deposits of aggregated proteins have long been associated with many neurodegenerative diseases. But this correlation leaves unanswered the most important questions: is the aggregation a cause or an effect of the disease, and how might aggregates exert a toxic gain of function to cause disease?
Now Neil Bence, Ron Kopito and colleagues from Stanford University (Stanford, CA) have found that protein aggregation impairs the function of the ubiquitin–proteasome system (UPS). Reduced UPS-mediated degradation of certain key substrates could lead to cell-cycle abnormalities and cell death, and indeed Bence et al. find evidence for a cell-cycle delay in cells with aggregates.
Their reporter for UPS function is an unstable form of GFP. Expression of aggregation-prone proteins leads to an increase in GFP reporter fluorescence, particularly in cells with large inclusions called aggresomes. In 1998, Kopito and colleagues discovered...
