The presence of RNA foci is a prominent feature of a group of deadly inherited neurodegenerative diseases, including Huntington's disease, certain
forms of amyotrophic lateral sclerosis (ALS), and frontotemporal dementia.
While many researchers believe that these clusters are toxic to nerve cells, it has not been clear how or why they form.
Published online recently in the journal Nature, the new study focused on a group of disorders known as "repeat expansion" diseases. In these conditions,
short strings of the deoxyribonucleic acid (DNA) "letters" known as nucleotides
are abnormally repeated several times.
Over the course of an individual's life, or across generations, the number of such repeats can expand, which may increase disease susceptibility and severity
within families.
Another suspect is messenger RNA, which is copied from the DNA and used by the cell to guide protein production.
Ronald Vale, professor in the UCSF's Department of Cellular and Molecular Pharmacology, who led the new research, and UCSF postdoctoral fellow Ankur Jain,
who performed the new experiments, found that each nucleotide repeat in RNA
behaves like a small piece of molecular Velcro, or fastener, that can stick to
repeats on other RNA strands.
"When you have lots of tandem pieces of Velcro, that allows one RNA strand to stick to multiple other strands with similar repeats," Vale said. "What you then
get is many RNAs binding to one another to form a tangled gel."
Jain and Vale demonstrated this phenomenon in purified RNA in a test tube as well as when they artificially induced production of these disease-causing RNAs
in cells in a dish.
"You start that process of making the RNA in cells and then can watch the gels forming in the nucleus in a time-lapse movie," Vale was quoted as saying in
a news release.
And the two researchers found that about 30 nucleotide repeats were needed to trigger formation of RNA gels, similar to the number of repeats associated with
the emergence of disease symptoms.
RNA gels did not form when Jain tested random nucleotide sequences that did not have disease-related repeating patterns.
In addition, while previous research indicated that RNA somehow combined with proteins to form foci, the new research suggests these clusters can arise from
RNA alone.
"We have contributed a new hypothesis of how RNA foci form in these disorders," said Vale. "Protein aggregation is a well-accepted cause of many
neurodegenerative diseases, including Alzheimer's and ALS, but our work suggests
that aggregation of RNA, by itself, might also be a culprit in
neurodegeneration."
"Now we want to tackle new therapeutics by focusing on strategies that act on RNA and that could dissolve these potentially pathological structures," he said.
Along with medical nutritional therapy and insulin, exercise is the third component to successfully treating diabetes. Exercise, like insulin, lowers
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