Antibiotic rifampicin shows promise for fighting Parkinsons disease in lab tests
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 Parkinsons 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 Parkinsons 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 Finks 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 Parkinsons 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.
Finks 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 Parkinsons disease when it is first diagnosed," he said.
The researchers used several different techniques to study the mechanism underlying rifampicins 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 Finks 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 Alzheimers 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 Alzheimers disease and with about one third of patients with Parkinsons disease. But no studies have looked specifically at Parkinsons disease in people taking this drug," Fink said.
Tim Stephens | EurekAlert!
The most recent press releases about innovation >>>
Die letzten 5 Focus-News des innovations-reports im Überblick:
At the productronica trade fair in Munich this November, the Fraunhofer Institute for Laser Technology ILT will be presenting Laser-Based Tape-Automated Bonding, LaserTAB for short. The experts from Aachen will be demonstrating how new battery cells and power electronics can be micro-welded more efficiently and precisely than ever before thanks to new optics and robot support.
Fraunhofer ILT from Aachen relies on a clever combination of robotics and a laser scanner with new optics as well as process monitoring, which it has developed...
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
New technique promises tunable laser devices
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...