Northwestern University scientists now offer a clue that may get to the core of the cell death question and establish a common mechanism in these diseases. In a study to be published online Feb. 9 by the journal Science, the research team shows that polyglutamine (the toxic component of the protein responsible for Huntington's disease) is so demanding on the cell's system that it changes the environment within the cell, causing other metastable, or partially folded, proteins to crash and lose function. Over time, this can cause the organism to die.
"Our results suggest that these disease-associated, aggregation-prone proteins may exert their destabilizing effects by interfering generally with other proteins that are having difficulty folding," said Richard I. Morimoto, Bill and Gayle Cook Professor of Biochemistry, Molecular Biology and Cell Biology, who led the study. Morimoto is an expert in Huntington's disease and on the cellular and molecular response to damaged proteins.
"We found that the system for protein quality control is not robust at all -- it is very delicate," said Morimoto. "Slight changes in the cell's environment have huge consequences. A single mutant polyglutamine protein interferes with the folding and functioning of very different types of proteins in the cell. This, in turn, could interfere with innumerable cellular processes and offers an explanation of why so many different mechanisms have been proposed for toxicity and cell death."
Morimoto speculates that it could be the misfolded protein's structure that, indirectly, is causing the other proteins to become non-functional. If so, these findings have implications for all neurodegenerative diseases. For each disease, a single or a small number of mutant proteins have been identified as causing the disease, and studies have shown that the misfolded states of these mutant proteins are all structurally related.
The experiments were conducted in C. elegans, a transparent roundworm whose biochemical environment is similar to that of human beings and whose genome, or complete genetic sequence, is known. The researchers picked seven random and unrelated proteins that are expressed in the same compartment in the cell as mutant polyglutamine. The seven metastable proteins -- each essential to the functioning of muscle, nerve or hypodermal cells -- had a temperature-sensitive mutation: the proteins are fine at normal temperature but when the temperature is elevated the mutation is expressed.
When the researchers introduced the toxic polyglutamine protein, the environment of the cell completely changed. In the case of each of the seven proteins, the presence of the expanded polyglutamine caused each mutation to be expressed at normal temperature. In turn, the metastable protein intensified the aggregation properties of the polyglutamine protein.
"These results could provide a very powerful tool for understanding all the neurodegenerative diseases," said Morimoto. "Do all proteins that cause this class of disease, such as mutant SOD in familial ALS or prions in Creutzfeldt-Jakob disease, have the same consequences? To find out, we plan to do the same experiments using the mutant proteins associated with the other diseases."
"This research suggests that a common mechanism may underlie a variety of protein folding diseases," said James Anderson, a geneticist at the National Institute of General Medical Sciences, at the National Institutes of Health, which partially funded the research. "While the hypothesis needs to be tested in other organisms, findings made in model organisms such as C. elegans are often the first step in understanding the molecular roots of human diseases."
In addition to Morimoto, other authors on the Science paper are post-doctoral fellows Tali Gidalevitz and Anat Ben-Zvi (co-first authors), undergraduate student Kim Ho, and recent Ph.D. recipient Heather R. Brignull, all from Northwestern University.
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