December 6, 2004
Antibiotic rifampicin shows promise for fighting
Parkinson's disease in laboratory tests
By Tim Stephens
UCSC researchers 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.
Postdoctoral researcher Jie Li studied the effects of the antibiotic rifampicin and other
factors on the formation of alpha-synuclein fibrils. Photo courtesy of the Chemistry and
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
"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,"
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 published in
the November issue of the journal Chemistry and Biology.
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.
Fibrils of alpha-synuclein, shown in this electron microscope image, are associated
with the death of brain cells in Parkinson's disease. Image: A. Fink
"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,"
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
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
"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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