Susan L. Lindquist can imagine several possible strategies for treating diseases caused by misfolded proteins: Scientists might find or design proteins or drugs that would bind to their sticky surfaces and prevent other molecules from getting trapped there. They might design proteins that could insert themselves between the aggregates and help break them up. They might alter the chaperone balance of the cell to help ensure that the proteins attain their correct shape. Or they could try to increase the activity of the cell's proteasome, a sort of garbage can in the cytoplasm that chews up misfolded proteins and gets rid of them.

A wide range of diseases might be treated with these approaches, she says. In addition to the 20 or so amyloid disorders and at least eight CAG-repeat diseases, Parkinson's disease is a candidate. There are some helpful treatments for Parkinson's today, but they do not get to the root of the disease, which involves aggregates of the alpha-synuclein protein. Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), too, has been shown to involve protein aggregates—in this case, the protein superoxide dismutase.

There is even hope of treating or stopping mad cow disease—bovine spongiform encephalitis, or BSE—before the disease spreads to large numbers of humans in the form of new-variant Creutzfeldt-Jakob disease. "I really do believe that most of these neurodegenerative diseases can be attacked," Lindquist says. "It may be five or ten years away, but we will be able to make a real difference. —MP

Photo: Todd Buchanan

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Reprinted from the HHMI Bulletin,
September 2001, pages 8-13.
©2001 Howard Hughes Medical Institute

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