"We believe that in neurodegenerative diseases there is a race between the body's emergency crew of heat shock proteins and the protein misfolding that drives the formation of dangerous aggregates in the cell," said Morimoto, who was first to clone a human heat shock gene in 1985. "When a more critical distress call arises in another part of the body -in the heart, for example -the heat shock proteins are diverted, giving the misfolded proteins a chance to develop into a protein aggregate. If the aggregate grows large enough, disease sets in and protein misfolding wins."
In Huntington's disease, for example, the mutated gene codes for a protein that produces an increasing number of consecutive residues of the amino acid glutamine. When the number of residues expands past 40, the protein becomes insoluble, causing the protein to misfold. This results in a loss of function and protein aggregation -in other words, disease. Humans without the mutated gene also may have an expansion of glutamine residues, but they remain healthy and unaffected because the number of residues in their cells never passes the dangerous 40 mark.
"Our model is the first to visually show the general principles underlying the behavior of polyglutamine expansions in cells," said Morimoto. "These findings help us better understand the progressive nature of neurodegenerative diseases, particularly Huntington's."
In order to visualize misfolded proteins and their behavior in an animal, Morimoto and his team studied polyglutamine expansions expressed in C. elegans, a transparent roundworm whose
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Contact: Megan Fellman
fellman@northwestern.edu
847-491-3115
Northwestern University
21-May-2000