Why is the altered form of huntingtin not broken down by the cell, as normally occurs with irregular proteins?
A recent Stanford University study suggests that protein aggregates impair UPS function, another explanation for how these huntingtin bundles can lead to the death of neurons. Large clumps of defective protein accumulate and scar neurons, which then cannot survive and reproduce. This conclusion about the relationship between protein aggregation, UPS function, and neurodegenerative disease was drawn from an experiment involving mutant cystic fibrosis protein and mutant huntingtin protein. Both of these proteins contain a polyglutamine repeat sequence, giving them the tendency to aggregate. Within human embryonic kidney cells, proteins were tagged with a special form of green fluorescent protein (GFP) which glows only when proteins remain intact. Throughout the experiment, mutant, aggregation-prone proteins continued to glow, showing that they were resistant to degradation, and thus, that the UPS system was stalled. Fluorescence was higher in cells containing aggregates than in cells without, suggesting that protein aggregation led to the UPS disruption.
Last Modified: 9-13-02
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