Posts tagged mRNA
Articles and news from the latest research reports.
Neurons are electrically charged cells, located in the nervous system, that interpret and transmit information using electrical and chemical signals. Now, researchers at the University of Missouri have determined that individual neurons can react differently to electrical signals at the molecular level and in different ways—even among neurons of the same type. This variability may be important in discovering underlying problems associated with brain disorders and neural diseases such as epilepsy.
“Genetic mutations found in neurological disorders create imbalances in the inward and outward flow of electrical current through cells,” said David Schulz, associate professor in the Division of Biological Sciences in the College of Arts and Science and a researcher in the Interdisciplinary Neuroscience Program at MU. “Often, neurons react to electrical signals, or voltage, and compensate by altering their own electrical outputs. The variability in these imbalances, even among multiple cells of the same kind within the brain, is one of the major problems scientists face when trying to design therapeutics for disorders like epilepsy. Seizures in individuals can be caused by different imbalances—therefore getting to the root of how neurons act individually makes our studies important.”
Schulz and his team previously proved that two identical neurons can reach the same electrical activity in different ways. In his new study, Schulz hypothesized that neurons might use the cell’s genetic code, or its messenger RNA (mRNA), to “fine tune” the production of proteins, helping individual cells react accordingly.
Using clusters of neurons obtained from Jonah crabs, Schulz and his team experimentally altered electrical input and output in the neurons and measured the messenger RNA (mRNA) levels found within the cells. Invertebrates like crabs are useful in neuroscience research because their neurons are simple enough to observe and study, but advanced enough that they can be “scaled up” to apply to higher organisms, Schulz said.
They found that when normal patterns of stimulation were maintained, cells engaged the correct ratios of mRNA to produce the proteins needed to help keep electrical impulses in order; however, when normal patterns of activity were not maintained, this fundamentally changed the cells at the molecular level.
“We were the first to show that the correct ratios of mRNAs are actively maintained by the actual activity or voltage of the cell, and not chemical feedback,” Schulz said. “These results represent a novel aspect of regulation that might be useful for developing therapeutics for neuronal disorders later.”
Schulz’ study, “Activity-dependent feedback regulates correlated ion channel mRNA levels in single identified motor neurons,” was published in the August 18th edition of Current Biology.
Neurons at work
Film editors play a critical role by helping shape raw footage into a narrative. Part of the challenge is that their work can have a profound impact on the finished product — with just a few cuts in the wrong places, comedy can become tragedy, or vice versa.
A similar process, “alternative splicing,” is at work inside the bodies of billions of creatures — including humans. Just as a film editor can change the story with a few cuts, alternative splicing allows cells to stitch genetic information into different formations, enabling a single gene to produce up to thousands of different proteins.
Harvard scientists say they’ve now been able to observe that process within the nervous system of a living creature.
Variation in bitter receptor mRNA expression affects taste perception
Do you love chomping on raw broccoli while your best friend can’t stand the healthy veggie in any form or guise? Part of the reason may be your genes, particularly your bitter taste genes.
Over the past decade, scientists at the Monell Center and elsewhere have made headway in understanding how variants of bitter taste receptor genes can help account for how people differ with regard to taste perception and food choice.
However, some perplexing pieces of the puzzle remained, as two people with exactly the same genetic makeup can still differ markedly regarding how bitter certain foods and liquids taste to them.
Now, findings from Monell reveal that a person’s sensitivity to bitter taste is shaped not only by which taste genes that person has, but also by how much messenger RNA – the gene’s instruction guide that tells a taste cell to build a specific receptor – their cells make.
Under normal circumstances, people whose taste receptor cells make more messenger RNA (mRNA) for a given gene make more of the encoded receptor.
The findings add a new level of complexity to our understanding of the cellular mechanisms of taste perception, which may ultimately lend insight into individual differences in food preferences and dietary choices.
"The amount of messenger RNA that taste cells choose to make may be the missing link in explaining why some people with ‘moderate-taster’ genes still are extremely sensitive to bitterness in foods and drinks," said Monell taste geneticist Danielle Reed, PhD, who is an author on the study.
In the study, reported online in the American Journal of Clinical Nutrition, small biopsies of papillae – the little bumps on the tongue that contain taste receptors – were taken from 18 people known to have the same moderate-taster (heterozygous) genotype for the TASR38 bitter taste receptor and the amount of mRNA expression for this genotype was measured.
Before the biopsy, people rated the intensity of various bitter and non-bitter solutions, including broccoli juice. Even though the subjects had the same ‘middle-of-the road’ genotype, their responses to some of the bitter substances varied over four orders of magnitude. Analyses revealed a direct relationship between mRNA expression and bitterness ratings of broccoli juice, with subjects having the most mRNA rating the juice as most bitter.
"The next step involves learning more about what causes these individual differences in mRNA expression; does diet drive expression or is it the reverse? And, can differences in expression explain why children are more sensitive to bitter than adults with the same genotype?" said co-author Julie Mennella PHD, a developmental psychobiologist at Monell.
Hospital scientists identify ALS disease mechanism
Study strengthens link between amyotrophic lateral sclerosis (ALS) and problems in protein production machinery of cells and identifies possible treatment strategy
Researchers have tied mutations in a gene that causes amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders to the toxic buildup of certain proteins and related molecules in cells, including neurons. The research, published recently in the scientific journal Cell, offers a new approach for developing treatments against these devastating diseases.
Scientists at St. Jude Children’s Research Hospital and the University of Colorado, Boulder, led the work.
The findings provide the first evidence that a gene named VCP plays a role in the break-up and clearance of protein and RNA molecules that accumulate in temporary structures called RNA granules. RNAs perform a variety of vital cell functions, including protein production. RNA granules support proper functioning of RNA.
In ALS and related degenerative diseases, the process of assembling and clearing RNA granules is impaired. The proteins and RNAs associated with the granules often build up in nerve cells of patients. This study shows how mutations in VCP might contribute to that process and neurodegenerative disease.
“The results go a long way to explaining the process that links a variety of neurodegenerative diseases, including ALS, frontotemporal dementia and related diseases of the brain, muscle and bone known as multisystem proteinopathies,” said the study’s co-corresponding author, J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. Roy Parker, Ph.D., of the University of Colorado’s Department of Chemistry and Biochemistry and the Howard Hughes Medical Institute (HHMI), is the other corresponding author.
ALS, also known as Lou Gehrig’s disease, is diagnosed in about 5,600 Americans annually and is associated with progressive deterioration of nerve cells in the brain and spine that govern movement, including breathing. There is no effective treatment, and death usually occurs within five years.
“A strength of this study is that it provides a unifying hypothesis about how different genetic mutations all affect stress granules, which suggests that understanding stress granule dynamics and how they can be manipulated might be beneficial for treatment of these diseases,” Parker said.
Earlier work from Taylor’s laboratory identified mutations in VCP as a cause of ALS and related multisystem proteinopathies. Until now, however, little was known about how those mistakes caused disease. The latest findings appeared in the June 20 issue and are highlighted in a review article published in the August 15 issue of Cell.
The research also ties VCP mutations to disruption of RNA regulation, which prior studies have connected to the progression of neurodegenerative diseases, said Regina-Maria Kolaitis, Ph.D., a postdoctoral fellow in Taylor’s laboratory. She and Ross Buchan, Ph.D., a postdoctoral fellow in Parker’s laboratory, are co-first authors.
The work focused on a class of RNA granules called stress granules. They are formed by proteins and an RNA molecule called mRNA that accumulates in the cell cytoplasm in response to stress. Stressed cells do not want to waste energy producing unnecessary proteins. Stress granules are one mechanism cells use to halt production until the cellular environment normalizes, which is when stress granules typically dissolve.
Proteins found in stress granules include RNA-binding proteins like TDP-43, FUS, hnRNPA1 and hnRNPA2B1 that regulate gene activity. Mutations in those proteins can also cause ALS and related disorders.
“VCP has many functions in cells, but it is not an RNA-binding protein and until now it was not connected to stress granules or RNA processing,” Kolaitis said. “This study provides a new window into the disease process, highlighting VCP’s role in keeping cells healthy.”
For this study, researchers used yeast to identify a network of 125 genes that affect the formation and behavior of stress granules. One of the genes that appeared to play a central role in the network was CDC48, which functions like VCP in yeast. In addition, many of the genes identified are involved in a process called autophagy that cells use to break down and recycle unneeded molecules, including proteins.
Working in yeast and mammalian cells, researchers showed that stress granules are cleared by autophagy, which stalled when VCP was mutated. Researchers also reported that stress granules accumulated following mutation of either CDC48 or VCP.
“This work suggests that activating autophagy to help rid cells of stress granules offers a new approach to neurodegenerative disease treatment,” Taylor said.
(Source: stjude.org)
A Genetic Answer to the Alzheimer’s Riddle?
What if we could pinpoint a hereditary cause for Alzheimer’s, and intervene to reduce the risk of the disease? We may be closer to that goal, thanks to a team at the University of Kentucky. Researchers affiliated with the UK Sanders-Brown Center on Aging have completed new work in Alzheimer’s genetics; the research is detailed in a paper published today in the Journal of Neuroscience.
Emerging evidence indicates that, much like in the case of high cholesterol, some Alzheimer’s disease risk is inherited while the remainder is environmental. Family and twin studies suggest that about 70 percent of total Alzheimer’s risk is hereditary.
Recently published studies identified several variations in DNA sequence that each modify Alzheimer’s risk. In their work, the UK researchers investigated how one of these sequence variations may act. They found that a “protective” genetic variation near a gene called CD33 correlated strongly with how the CD33 mRNA was assembled in the human brain. The authors found that a form of CD33 that lacked a critical functional domain correlates with reduced risk of Alzheimers disease. CD33 is thought to inhibit clearance of amyloid beta, a hallmark of Alzheimers disease.
The results obtained by the UK scientists indicate that inhibiting CD33 may reduce Alzheimer’s risk. A drug tested for acute myeloid leukemia targets CD33, suggesting the potential for treatments based on CD33 to mitigate the risk for Alzheimer’s disease. Additional studies must be conducted before this treatment approach could be tested in humans.
Rhythmic Changes in Gene Activation Power the Circadian Clock
Rhythms underlie the daily functions of mammals, from sleep-wake cycles to metabolic processes in the liver. The circadian clock has evolved in response to daily changes in temperature and light in the environment. At the root of circadian rhythms are daily fluctuations in gene expression, which occur in part through the process of transcription—the creation of RNA from sequences of DNA. Although past studies have uncovered how changes in transcription states relate to irreversible processes, for example when cells become more specialized, much less is known about how transcription fluctuates in synch with recurring cycles.