Researchers at the University of California, Santa Cruz, have shown that rifampicin, an antibiotic used to treat leprosy and tuberculosis, can prevent the formation of protein fibrils associated with the death of brain cells in people with Parkinson's disease. The drug also dissolved existing fibrils in laboratory tests.
The researchers studied the effects of rifampicin in test tube experiments and are currently doing studies with cell cultures and mice to see if the same effects occur in living cells. Although these are just the first steps along the path toward clinical studies in humans, the findings suggest that rifampicin and related compounds might be effective in preventing fibril formation and associated neurological damage in patients with Parkinson's disease, said Anthony Fink, professor of chemistry and biochemistry at UCSC.
"Clearly, more work is needed to determine if this would work therapeutically, but if it does it would probably be most useful as a prophylactic therapy used in the early stages of the disease before there is general neurological damage," Fink said.
The research was carried out by a team of scientists in Fink's lab, including postdoctoral researchers Jie Li, Min Zhu, and Sudha Rajamani and research associate Vladimir Uversky. Li is first author of a paper describing their results in the November issue of the journal Chemistry and Biology, which is mailed and published online on November 29.
Aggregation of the protein known as alpha-synuclein into insoluble fibrils is thought to be a critical step in the development of Parkinson's disease, a progressive movement disorder resulting from the death of nerve cells in the brain that produce the neurotransmitter dopamine. Deposits called Lewy bodies, composed mostly of alpha-synuclein fibrils, appear in affected nerve cells, but the connection between the fibrils and cell death remains controversial, Fink said.
"There are two schools of thought: One is that the fibrils themselves are toxic, and the other is that smaller precursors of the fibrils formed earlier in the process are toxic and cause the neurons to die," he said.
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 protein from alpha-synuclein. In addition, epidemiological studies of leprosy patients have indicated that patients treated for several years with rifampicin had a lower probability of developing senile dementia.
"Dementia is associated with Alzheimer's disease and with about one third of patients with Parkinson's disease. But no studies have looked specifically at Parkinson's disease in people taking this drug," Fink said.
Fink's research on alpha-synuclein is supported by a grant from the National Institutes of Health.
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Note to reporters: You may contact Fink at (831) 459-2744 or enzyme@ucsc.edu.
