Proteins are the molecular machines of the cell. They transport
materials, cleave products or transmit signals -- and for a long time,
they have been a main focus of attention in molecular biology research.
In the last two decades, however, another class of critically important
molecules has emerged: small RNA molecules, including micro-RNAs. It is
now well established that micro-RNAs play a key role in the regulation
of cell function."A micro-RNA regulates the production of an estimated
300-400 proteins.
This class of molecules can be regarded as a switch that coordinates
the transition of cells from one state to another," explains Prof. Dr.
André Fischer, scientist at the German Center for Neurodegenerative
Diseases (DZNE) and Speaker of the DZNE site Göttingen. He and his team
have identified a micro-RNA that regulates the learning processes and
probably plays a central role in Alzheimer's disease. The researchers
have shown that there is too much of a micro-RNA called "miRNA 34c" in
mouse models of Alzheimer's disease, and decreasing the level of miRNA
34c in these mice can restore their learning ability. The scientists
have identified a new target molecule that might be important for
diagnosis and treatment of Alzheimer's disease. The studies were carried
out in collaboration with scientists at the European Neuroscience
Institute Göttingen, the Göttingen University, the DZNE site in Munich
and researchers from Switzerland, USA and Brazil.
miRNA 34c was identified using a highly complex method called
"massive parallel sequencing." With this technology, Fischer and his
colleagues captured the complete RNA composition in the hippocampus --
the learning region of the brain -- and compared this with the RNA of
the entire brain. They showed that miRNA 34c is enriched in the
hippocampus, especially in during the time window of a few hours after a
learning phase. "We suspect that the function of micro-RNA 34c is to
switch off a whole range of gene products that are turned on in the
learning process," Fischer said. Too much miRNA 34c would then lead to a
blockade of learning -- which is exactly what was shown in subsequent
experiments.
In old mice, which do not learn as easily as their younger
counterparts, there was indeed too much miRNA 34c. The miRNA-34c level
was also elevated in mice that are used as specific research models of
Alzheimer's disease. These mice carry a genetic mutation that can cause
Alzheimer's in humans and show disturbances of memory function.
Moreover, miRNA 34c seems to not only play a role in mice. Fischer and
his colleagues showed these levels are also elevated in the brains of
Alzheimer's patients.
In further mouse experiments, the researchers showed that miRNA 34c
is actually causally involved in the pathogenesis of Alzheimer's disease
and memory disorders. An artificial increase of miRNA-34c level in
normal mice results in memory impairment in the animals. Secondly, as
Fischer and his colleagues have shown, lowering miRNA-34c levels can
restore learning ability in mouse models of Alzheimer's disease and in
older mice. "Neurodegenerative diseases like Alzheimer's are associated
with many factors. We hope that with the identification of micro-RNA
34c, we have found an important mediator of pathogenesis," says Fischer.
"Micro-RNA 34c would then be a good candidate for the development of
drugs against Alzheimer's."
Athanasios Zovoilis, Hope Y Agbemenyah, Roberto C Agis-Balboa, Roman M
Stilling,Dieter Edbauer, Pooja Rao, Laurent Farinelli, Ivanna Delalle,
Andrea Schmitt, Peter Falkai, Sanaz Bahari-Javan, Susanne Burkhardt,
Farahnaz Sananbenesi1 & Andre Fischer. Micro-RNA-34C is a novel target to treat dementias. EMBO Journal, 2011.327
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