Fink's group found that rifampicin stabilized alpha-synuclein in a soluble form, both as single molecules and in small, soluble clumps of the protein, thereby preventing the formation of fibrils. Furthermore, addition of the drug to already-formed fibrils of alpha-synuclein resulted in disaggregation of the fibrils into soluble clumps and single molecules. Fink noted that preliminary data from experiments in cell cultures and in mice indicate that the soluble clumps of alpha-synuclein formed in the presence of rifampicin are nontoxic.
"The disaggregation of existing fibrils is probably the most interesting and novel finding in this study. If it works in people, that would really open up the possibility of stopping the progression of Parkinson's disease when it is first diagnosed," he said.
The researchers used several different techniques to study the mechanism underlying rifampicin's effects on alpha-synuclein. They found that the drug and its breakdown products bind tightly to alpha-synuclein, possibly even reacting with it to form a stable compound.
Their findings with rifampicin are very similar to previous research in Fink's lab with the compound baicalein, a flavonoid that also inhibits fibril formation and disaggregates existing fibrils of alpha-synuclein. Those results were published in June in the Journal of Biological Chemistry.
"We wanted to look at rifampicin because it is an already-approved drug that is similar to baicalein in key parts of its molecular structure," Fink said.
Research in other laboratories has found that rifampicin may also prevent the formation of the protein deposits that characterize Alzheimer's disease, which are composed of a different p
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Contact: Tim Stephens
stephens@ucsc.edu
831-459-4352
University of California - Santa Cruz
29-Nov-2004