University of Oregon researchers have shed new light on the function of an RNA-regulating protein known as muscleblind, which when it misbehaves and binds to rogue RNA can lead to disease affecting roughly one in 8,000 people.
The study, which used a combination of biochemical, biophysical and cell culture studies, was placed online ahead of regular publication in the December issue of the journal RNA. When the findings were initially presented in September at the annual meeting of the Myotonic Dystrophy Foundation in Italy, the work garnered a $1,000 cash prize for outstanding research for lead author Bryan Warf, a UO doctoral student.
Misbehaving RNA can lead to myotonic dystrophy, an inherited condition that affects muscles and other body systems. It is the most commonly occurring form of adult onset muscular dystrophy with progressive muscle wasting as well as a variety of symptoms. An early symptom is the inability of muscles to relax after a simple handshake or gripping of a doorknob. It also can lead to cataracts, cardiac arrhythmia, insulin resistance and male infertility. It can be life-threatening in cases of early onset, particularly in children. Researchers believe that the numbers of a specific type of nucleotide expansions in a person's DNA gives rise to myotonic dystrophy.
The UO findings apply to both known forms: DM1, which can manifest at any point in life, from birth to late 60s; and DM2, which more commonly surfaces in adulthood. While independent genes are responsible in each form, the same protein's interaction with RNA in the genes is implicated in both diseases.
"In a simplistic view, this disease is about this protein not functioning properly," Warf said. "So we've been trying to see what this protein does normally to keep us healthy and promote healthy development."
In their study, Warf and Andy Berglund, professor of chemistry and member of the Institute of Molecular Biology, focused on the RNA-splicing protein muscleblind-like (MBNL) and its interactions with both normal strands of RNA and disease-causing RNA that contains mismatched pairs of repeat nucleotides. RNA (ribonucleic acid) is much like translation software, a driver that serves as a messenger between DNA and proteins.
"Toxic RNA," as Berglund describes the mutated strands in the genome, is like a sentence that contains many extra misplaced copies of the word "the" within it. In their paper, Warf and Berglund found that MBNL binds to both normal and toxic forms of RNA. When bound to the toxic versions, MBNL ignores its other RNA targets and does not help process them normally, leading to disease. In earlier work, Berglund's lab solved the crystal structure of the toxic RNA.
In this new study, Warf and Berglund tested MBNL's interactions with both normal RNA and toxic RNA. They found that muscleblind has no preference for a toxic RNA that contains any type of pyrimidine-pyrimidine mismatch. Warf and Berglund were the first to articulate the structure of one of MBNL's normal RNA targets. It had been thought that the structure of the toxic RNA was much different than the structure of a normal RNA target for MBNL, but Warf and Berglund showed that the two structures are actually quite similar.
"Through his studies," Berglund said, "Bryan has provided insight into how muscleblind may normally function. The dogma was that this protein was recognizing a complex structure in the toxic RNA, and normally it was recognizing a more simple RNA structure in regulating splicing. Bryan found the RNA that is normally recognized actually adopts a structure that looks a lot like the toxic RNA. Muscleblind recognizes both. The diseased RNA is mimicking the natural RNA."
The work was funded by a grant to Berglund from the Muscular Dystrophy Association, grants from the National Institutes of Health to Berglund and to Warf's co-adviser Peter H. von Hippel, professor of biophysical chemistry and molecular biology, and an NIH training grant to the UO Institute of Molecular Biology.
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