Aggregates of proteins are a common feature in many neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, fronto-temporal dementia and ALS. Their role in contributing to these diseases remains unclear. Normally, cells dispose of the unwanted protein clumps by tagging them with ubiquitin, which then are destroyed by a complex called the proteasome. In today's Science, Neil Bence and colleagues report that once the aggregates are formed, the aggregates themselves seem to almost completely block the ubiquitin-proteasome system from working. They showed this to be the case with two different proteins, the pathogenic form of huntingtin and a folding mutant of cystic fibrosis transmembrane conductance regulator. The authors write: "Because of the central role of ubiquitin-dependent proteolysis in regulating fundamental events such as cell division and apoptosis, our data suggest a potential mechanism linking proein aggregation to cellular disregulation and cell death." The relevance of this mechanism to Alzheimer's disease may be disputed. Unlike aggregating proteins in other major neurodegenerative diseases, Aβ aggregates (a hallmark of Alzheimer's disease) are largely found outside the cell. However, some researchers suggest that Aβ also aggregates within the neuron.
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- Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 2001 May 25;292(5521):1552-5. PubMed.