Posts tagged RNA splicing
Articles and news from the latest research reports.
New Link Found Between Obesity and Insulin Resistance
Obesity is the main culprit in the worldwide avalanche of type 2 diabetes. But how excess weight drives insulin resistance, the condition that may lead to the disease, is only partly understood. Scientists at Joslin Diabetes Center now have uncovered a new way in which obesity wreaks its havoc, by altering the production of proteins that affect how other proteins are spliced together. Their finding, published in Cell Metabolism, may point toward novel targets for diabetes drugs.
Scientists in the lab of Mary-Elizabeth Patti, M.D., began by examining the levels of proteins in the livers of obese people, and finding decreases in number for certain proteins that regulate RNA splicing.
“When a gene is transcribed by the cell, it generates a piece of RNA,” explains Dr. Patti, who is also an Assistant Professor of Medicine at Harvard Medical School. “That piece of RNA can be split up in different ways, generating proteins that have different functions.”
“In the case of these proteins whose production drops in the livers of obese people, this process changes the function of other proteins that can cause excess fat to be made in the liver,” she adds. “That excess fat is known to be a major contributor to insulin resistance.”
Additionally, the researchers showed that these RNA splicing proteins are diminished in samples of muscle from obese people.
The investigators went on to examine a representative RNA-splicing protein called SFRS10 whose levels drop in muscle and liver both in obese people and in over-fed mice. Working in human cells and in mice, they demonstrated that SFRS10 helps to regulate a protein called LPIN1 that plays an important role in synthesizing fat. Among their results, mice in which they suppressed production of SFRS10 made more triglycerides, a type of fat circulating in the blood.
“More broadly, this work adds a novel insight into how obesity may induce insulin resistance and diabetes risk by changing critical functions of cells, including splicing,” says Dr. Patti. “This information should stimulate the search for other genes for which differences in splicing may contribute to risk for type 2 diabetes. Ultimately, we hope that modifying these pathways with nutritional or drug therapies could limit the adverse consequences of obesity.”
(Source: joslin.org)
Alzheimer’s: newly identified protein pathology impairs RNA splicing
Researchers at Emory University School of Medicine’s Alzheimer’s Disease Research Center have identified a previously unrecognized type of pathology in the brains of patients with Alzheimer’s disease.
These tangle-like structures appear at early stages of Alzheimer’s and are not found in other neurodegenerative diseases such as Parkinson’s disease.
What makes these tangles distinct is that they sequester proteins involved in RNA splicing, the process by which instructional messages from genes are cut and pasted together. The researchers show that the appearance of these tangles is linked to widespread changes in RNA splicing in Alzheimer’s brains compared to healthy brains.
The finding could change scientists’ understanding of how the disease develops and progresses, by explaining how genes that have been linked to Alzheimer’s contribute their effects, and could lead to new biomarkers, diagnostic approaches, and therapies.
The results are published in the Proceedings of the National Academy of Sciences, Early Edition.
"We were very surprised to find alterations in proteins that are responsible for RNA splicing in Alzheimer’s, which could have major implications for the disease mechanism," says Allan Levey, MD, PhD, chair of neurology at Emory University School of Medicine and director of the Emory ADRC.
"This is a brand new arena," says James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. "Many Alzheimer’s investigators have looked at how the disease affects alternative splicing of individual genes. Our results suggest a global distortion of RNA processing is taking place."
This research was led by Drs. Levey, Lah, and Junmin Peng, PhD, who was previously associate professor of genetics at Emory and is now a faculty member at St Jude Children’s Research Hospital. They were aided by collaborators at University of Kentucky, Rush University, and University of Washington as well as colleagues at Emory.
Accumulations of plaques and tangles in the brains of patients with Alzheimer’s disease were first observed more than a century ago. Investigating the proteins in these pathological structures has been central to the study of the disease.
Most experimental treatments for Alzheimer’s have aimed at curbing beta-amyloid, an apparently toxic protein fragment that is the dominant component of amyloid plaques. Other approaches target the abnormal accumulation of the protein tau in neurofibrillary tangles. Yet the development of Alzheimer’s is not solely explained by amyloid and tau pathologies, Lah says.
"Two individuals may harbor similar amounts of amyloid plaques and tau tangles in their brains, but one may be completely healthy while the other may have severe memory loss and dementia," he says.
These discrepancies led Emory investigators to take a “back to basics” proteomics approach, cataloguing the proteins that make up insoluble deposits in the brains of Alzheimer’s patients.
"The Alzheimer’s field has been very focused on amyloid and tau, and we wanted to use today’s proteomics technologies to take a comprehensive, unbiased approach," Levey says.
The team identified 36 proteins that were much more abundant in the detergent-resistant deposits in brain tissue from Alzheimer’s patients. This list included the usual suspects: tau and beta-amyloid. Also on the list were several “U1 snRNP” proteins, which are involved in RNA splicing.
These U1 proteins are normally seen in the nucleus of normal cells, but in Alzheimer’s brains they accumulated in tangle-like structures. Accumulation of insoluble U1 protein was seen in samples from patients with mild cognitive impairment (MCI), a precursor stage to Alzheimer’s, but the U1 pathology was not seen in any other brain diseases that were examined.
According to Chad Hales, MD, PhD, one of the study’s lead authors, “U1 aggregation is occurring early in the disease, and U1 tangles can be seen independently of tau pathology. In some cases, we see accumulation of insoluble U1 proteins before the appearance of insoluble tau, suggesting that it is a very early event.”
For most genes, after RNA is read out from the DNA (transcription), some of the RNA must be spliced out. When brain cells accumulate clumps of U1 proteins, that could mean the process of splicing is impaired. To test this, the Emory team examined RNA from the brains of Alzheimer’s patients. In comparison to RNA from healthy brains, more of the RNA from Alzheimer’s brain samples was unspliced.
The finding could explain how many genes that have been linked to Alzheimer’s are having their effects. In cells, U1 snRNP plays multiple roles in processing RNA including the process of alternative splicing, by which one gene can make instructions for two or more proteins.
"U1 dysfunction might produce changes in RNA processing affecting many genes or specific changes affecting a few key genes that are important in Alzheimer’s," Lah says. "Understanding the disruption of such a fundamental process will almost certainly identify new ways to understand Alzheimer’s and new approaches to treating patients."
Evolution: It’s all in how you splice it
MIT biologists find that alternative splicing of RNA rewires signaling in different tissues and may often contribute to species differences.
When genes were first discovered, the canonical view was that each gene encodes a unique protein. However, biologists later found that segments of genes can be combined in different ways, giving rise to many different proteins.
This phenomenon, known as alternative RNA splicing, often alters the outputs of signaling networks in different tissues and may contribute disproportionately to differences between species, according to a new study from MIT biologists.
After analyzing vast amounts of genetic data, the researchers found that the same genes are expressed in the same tissue types, such as liver or heart, across mammalian species. However, alternative splicing patterns — which determine the segments of those genes included or excluded — vary from species to species.
“The core things that make a heart a heart are mostly determined by a heart-specific gene expression signature. But the core things that make a mouse a mouse may disproportionately derive from splicing patterns that differ from those of rats or other mammals” says Chris Burge, an MIT professor of biology and biological engineering, and senior author of a paper on the findings in the Dec. 20 online edition of Science.
Lead author of the paper is MIT biology graduate student Jason Merkin. Other authors are Caitlin Russell, a former technician in Burge’s lab, and Ping Chen, a visiting grad student at MIT.