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Molecular mechanism sheds light on neurodegenerative diseases

EVANSTON, Ill. --- Alzheimer's. Parkinson's. Lou Gehrig's. Huntington's. These neurodegenerative diseases exhibit loss of nerve function in different ways, from memory lapses to uncontrollable muscular movements, but it is now believed that these diseases share many common molecular mechanisms.

A team of Northwestern University scientists, led by Richard I. Morimoto, John Evans Professor of Biology, has made a key discovery toward understanding one of these mechanisms. In studying toxic proteins involved in Huntington's disease, they discovered that the disease-causing protein severely interferes with the working of the proteasome, the cellular machine responsible for eliminating damaged proteins within the cell.

The findings, which could lead to an understanding of how to prevent neurodegenerative diseases and to the development of effective drugs, will be published Oct. 27 in The EMBO Journal, a publication of the European Molecular Biology Organization.

The proteasome is responsible for cell homeostasis. In healthy cells, proteins perform their function and then, with the help of the proteasome, disappear. If idle and damaged proteins remain, their presence can affect cell behavior.

Misfolded and damaged proteins are common to all human neurodegenerative diseases. They clump together to form toxic aggregates that destroy cell function and cause disease. Morimoto's team is the first to demonstrate in living human cells and in real time that the toxic protein aggregates, in this case caused by mutant Huntingtin, bind to the proteasome machine irreversibly and prevent the complete degradation of the proteins. This evidence could help explain the disease process.

"We believe this suggests why Huntington's disease is so destructive," said Morimoto. "Once bound, the toxic proteins do not release the proteasome. This interference with the normal clearance of proteins has a cumulative and amplifying negative effect. The protei
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Contact: Megan Fellman
fellman@northwestern.edu
847-491-3115
Northwestern University
21-Oct-2004


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