Posts Tagged ‘RNA’

Methyl chemical groups dot lengths of DNA, helping to control when certain genes are accessible by a cell. In new research, UCLA scientists have shown that at the connections between brain cells—which often are located far from the central control centers of the cells—methyl groups also dot chains of RNA. This methyl markup of RNA molecules is likely key to brain cells’ ability to quickly send signals to other cells and react to changing stimuli in a fraction of a second.

To dictate the biology of any cell, DNA in the cell’s nucleus must be translated into corresponding strands of RNA. Next, the messenger RNA, or mRNA—an intermediate genetic molecule between DNA and proteins—is transcribed into proteins. If a cell suddenly needs more of a protein—to adapt to an incoming signal, for instance—it must translate more DNA into mRNA. Then it must make more proteins and shuttle them through the cell to where they are needed. This process means that getting new proteins to a distant part of a cell, like the synapses of neurons where signals are passed, can take time.

Research has recently suggested that methyl chemical groups, which can control when DNA is transcribed into mRNA, are also found on strands of mRNA. The methylation of mRNA, researchers hypothesize, adds a level of control to when the mRNA can be translated into proteins, and their occurrence has been documented in a handful of organs throughout the bodies of mammals. The pattern of methyls on mRNA in any given cell is dubbed the “epitranscriptome.”

UCLA and Kyoto University researchers mapped out the location of methyls on mRNA found at the synapses, or junctions, of mouse brain cells. They isolated brain cells from adult mice and compared the epitranscriptome found at the synapses to the epitranscriptomes of mRNA elsewhere in the cells. At more than 4,000 spots on the genome, the mRNA at the synapse was methylated more often. More than half of these spots, the researchers went on to show, are in genes that encode proteins found mostly at the synapse. The researchers found that when they disrupted the methylation of mRNA at the synapse, the brain cells didn’t function normally.

The methylation of mRNA at the synapse is likely one of many ways that neurons speed up their ability to send messages, by allowing the mRNA to be poised and ready to translate into proteins when needed.

The levels of key proteins at synapses have been linked to a number of psychiatric disorders, including autism. Understanding how the epitranscriptome is regulated, and what role it plays in brain biology, may eventually provide researchers with a new way to control the proteins found at synapses and, in turn, treat disorders characterized by synaptic dysfunction.

More information: Daria Merkurjev et al. Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts, Nature Neuroscience (2018). DOI: 10.1038/s41593-018-0173-6

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By Ashley Yeager

Researchers have transferred a memory from one snail to another via RNA, they report today (May 14) in eNeuro. If confirmed in other species, the finding may lead to a shift in scientists’ thinking about how memories are made—rather than cemented in nerve-cell connections, they may be spurred on by RNA-induced epigenetic changes.

“The study suggests that RNA populations are the missing link in the search for memory,” Bridget Queenan, a neuroscientist at the University of California, Santa Barbara, who was not involved in the study, writes in an email to The Scientist. “If circulating neural RNAs can transfer behavioral states and tendencies, orchestrating both the transient feeling and the more permanent memory, it suggests that human memory—just like mood—will only be explained by exploring the interplay between bodies and brains.”

For decades, researchers have tried to pinpoint how, when, and where memories form. In the 1940s, Canadian psychologist Donald Hebb proposed memories are made in the connections between neurons, called synapses, and stored as those connections grow stronger and more abundant. Experiments in the 1960s, however, suggested RNA could play a role in making memories, though the work was largely written off as irreproducible.

Study coauthor David Glanzman of the University of California, Los Angeles, has been working on the cell biology of learning and memory for nearly 40 years, and says for the majority of that time he believed memory was stored at synapses. Several years ago, though, he and his colleagues began replicating memory-erasing research done in rodents in California sea hares (Aplysia californica), a type of marine snail also called a sea slug. The team found that the snail synapses built to “store” a memory weren’t necessarily the synapses that were removed from the neural circuits in the memory-erasing experiments.

“It was completely arbitrary which synaptic connections got erased,” Glanzman says. “That suggested maybe the memory wasn’t stored at the synapse but somewhere else.”

Glanzman turned his attention to RNA because of those earlier hints it was related to memory, and also because of recent experiments suggesting long-term memory was stored in the cell bodies of neurons, not synapses. He picked Aplysia because it has been a longtime model organism for memory studies. Like all mollusks, these snails have groups of neurons called ganglia, rather than brains. Their nervous systems comprise about 20,000 neurons, and the cells are some of the biggest and easily identifiable among nerve cells in all animals. In the snail’s gut, for example, are specific sensory and motor neurons that control the withdrawal of a fleshy, spout-like organ on the snail’s back called a siphon and the contraction of a caterpillar-looking gill, which the animal uses to breathe.

When touched lightly on the siphon, the neurons fire, retract the tissue, and contract the gill within the body cavity for a few seconds to protect it against attack. Sticking electrodes in the snail’s tail and shocking it makes this defensive response last longer, tens of seconds, and sometimes up to almost a minute. By repeatedly shocking the snail’s tail, the animal learns to stay in that defensive position when touched on the siphon, even weeks after the shocks end.

In his team’s latest experiments, Glanzman and his colleagues zapped snails’ tails, then pulled the abdominal neurons from the shocked snails, extracted their RNA, dissolved the RNA into deionized water, and injected the solution into the necks of snails that had never been shocked. (For a control, the team also took RNA from non-shocked snails and injected into naive snails.) When tapped on the siphon 24 hours later, snails that got RNA from shocked snails withdrew their siphon and gill for significantly longer (almost 40 seconds) than did snails that got RNA from non-shocked animals (less than 10 seconds).

DNA methylation appeared to be essential for the transfer of the memory among snails. When Glanzman and his colleagues blocked DNA methylation in snails getting RNA from shocked ones, the injected snails withdrew their siphons for only a few seconds when tapped on the siphon.

Glanzman wanted to know if the RNA from shocked snails actually affected the neuronal connections of the snails receiving the injections any differently than RNA from nonshocked snails. So, in a third test, he and his team removed sensory neurons from nonshocked snails, cultured the cells in a dish, and then exposed the cells to RNA from shocked snails. Zapping the culture with a bit of current excited the sensory neurons much more than neurons treated with RNA from nonshocked snails. RNA from shocked snails also enhanced a subset of synapses between sensory and motor neurons in vitro, suggesting it was indeed the RNA that transported the memory, Glanzman explains.

The idea “seems quite radical as we don’t have a specific mechanism for how it works in a non-synaptic manner,” Bong-Kiun Kaang, a neuroscientist at Seoul National University who was not involved in the study, writes in an email to The Scientist. Kaang notes there are “many critical questions that need to be addressed to further validate the author’s argument,” such as what kinds of noncoding RNAs are specifically involved, how are the RNAs transferred among neurons, and how much do RNAs at the synapse play a role? The experiments should also be replicated in organisms other than snails, he says.

Glanzman says that in his next experiments he will attempt to identify the RNAs involved, and he has an idea for the mechanism, too. The memory is not stored in the RNA itself, he speculates—instead, noncoding RNA produces epigenetic changes in the nucleus of neurons, thereby storing the memory.

“This idea is probably going to strike most of my colleagues as extremely improbable,” Glanzman says. “But if we’re right, we’re just at the beginning of understanding how memory works.”

A. Bédécarrats et al., “RNA from trained Aplysia can induce an epigenetic engram for long-term sensitization in untrained Aplysia,” eNeuro,, 2018.

St. Jude Children’s Research Hospital scientists have linked disruption of a brain circuit associated with schizophrenia to an age-related decline in levels of a single microRNA in one brain region

St. Jude Children’s Research Hospital scientists have identified a small RNA (microRNA) that may be essential to restoring normal function in a brain circuit associated with the “voices” and other hallucinations of schizophrenia. The microRNA provides a possible focus for antipsychotic drug development. The findings appear today in the journal Nature Medicine.

The work was done in a mouse model of a human disorder that is one of the genetic causes of schizophrenia. Building on previous St. Jude research, the results offer important new details about the molecular mechanism that disrupts the flow of information along a neural circuit connecting two brain regions involved in processing auditory information. The findings also provide clues about why psychotic symptoms of schizophrenia are often delayed until late adolescence or early adulthood.

“In 2014, we identified the specific circuit in the brain that is targeted by antipsychotic drugs. However, the existing antipsychotics also cause devastating side effects,” said corresponding author Stanislav Zakharenko, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. “In this study, we identified the microRNA that is a key player in disruption of that circuit and showed that depletion of the microRNA was necessary and sufficient to inhibit normal functioning of the circuit in the mouse models.

“We also found evidence suggesting that the microRNA, named miR-338-3p, could be targeted for development of a new class of antipsychotic drugs with fewer side effects.”

There are more than 2,000 microRNAs whose function is to silence expression of particular genes and regulate the supply of the corresponding proteins. Working in a mouse model of 22q11 deletion syndrome, researchers identified miR-338-3p as the microRNA that regulates production of the protein D2 dopamine receptor (Drd2), which is the prime target of antipsychotics.

Individuals with the deletion syndrome are at risk for behavior problems as children. Between 23 and 43 percent develop schizophrenia, a severe chronic disorder that affects thinking, memory and behavior. Researchers at St. Jude are studying schizophrenia and other brain disorders to improve understanding of how normal brains develop, which provides insights into the origins of diseases like cancer.

The scientists reported that Drd2 increased in the brain’s auditory thalamus when levels of the microRNA declined. Previous research from Zakharenko’s laboratory linked elevated levels of Drd2 in the auditory thalamus to brain-circuit disruptions in the mutant mice. Investigators also reported that the protein was elevated in the same brain region of individuals with schizophrenia, but not healthy adults.

Individuals with the deletion syndrome are missing part of chromosome 22, which leaves them with one rather than the normal two copies of more than 25 genes. The missing genes included Dgcr8, which facilitates production of microRNAs.

Working in mice, researchers have now linked the 22q11 deletion syndrome and deletion of a single Dgcr8 gene to age-related declines in miR-338-3p in the auditory thalamus. The decline was associated with an increase in Drd2 and reduced signaling in the circuit that links the thalamus and auditory cortex, a brain region implicated in auditory hallucination. Levels of miR-338-3p were lower in the thalamus of individuals with schizophrenia compared to individuals of the same age and sex without the diagnosis.

The miR-338-3p depletion did not disrupt other brain circuits in the mutant mice, and the findings offer a possible explanation. Researchers found that miR-338-3p levels were higher in the thalamus than in other brain regions. In addition, miR-338-3p was one of the most abundant microRNAs present in the thalamus.

Replenishing levels of the microRNA in the auditory thalamus of mutant mice reduced Drd2 protein and restored the circuit to normal functioning. That suggests that the microRNA could be the basis for a new class of antipsychotic drugs that act in a more targeted manner with fewer side effects. Antipsychotic drugs, which target Drd2, also restored circuit function.

The findings provide insight into the age-related delay in the onset of schizophrenia symptoms. Researchers noted that microRNA levels declined with age in all mice, but that mutant mice began with lower levels of miR-338-3p. “A minimum level of the microRNA may be necessary to prevent excessive production of the Drd2 that disrupts the circuit,” Zakharenko said. “While miR-338-3p levels decline as normal mice age, levels may remain above the threshold necessary to prevent overexpression of the protein. In contrast, the deletion syndrome may leave mice at risk for dropping below that threshold.”

The study’s first authors are Sungkun Chun, Fei Du and Joby Westmoreland, all formerly of St. Jude. The other authors are Seung Baek Han, Yong-Dong Wang, Donnie Eddins, Ildar Bayazitov, Prakash Devaraju, Jing Yu, Marcia Mellado Lagarde and Kara Anderson, all of St. Jude.

In our cells, proteins are the tiny machines that do most of the work. And the instructions for making proteins — and for piecing together their building blocks, called amino acids — are laid out by DNA, then relayed through RNA. But now, researchers show for the first time that amino acids can be assembled by another protein — without genetic instructions. These surprising findings were published in Science this week.

If a cell is an automobile-making factory, then ribosomes are the machines on the protein assembly line that links together amino acids in an order specified by DNA and messenger RNA (mRNA), an intermediate template. If something goes awry and a ribosome stalls, the quality control team shows up to disassemble the ribosome, discard that bit of genetic blueprint, and recycle the partially-made protein.

Turns out, that assembly line can keep going even if it loses its genetic instructions, according to a large U.S. team led by University of Utah, University of California, San Francisco, and Stanford researchers. They discovered an unexpected mechanism of protein synthesis where a protein, and not the normal genetic blueprint, specifies which amino acids are added.

“In this case, we have a protein playing a role normally filled by mRNA,” UCSF’s Adam Frost says in a news release. “I love this story because it blurs the lines of what we thought proteins could do.”

Frost and colleagues found a never-before-seen role for one member of the quality control team: a protein named Rqc2, which helps recruit transfer RNA (tRNA) to sites of ribosomal breakdowns (tRNA is responsible for bringing amino acids to the protein assembly line). Before the incomplete protein gets recycled, Rqc2 prompts the stalled ribosomes to add two amino acids — alanine and threonine — over and over. And that’s because the Rqc2–ribosome complex binds tRNAs that carry those two specific amino acids. In the auto analogy, the assembly line keeps going despite having lost its instructions, picking up whatever it can and attaching it in no particular order: horn-wheel-wheel-horn-wheel-wheel-wheel-wheel-horn, for example.

Pictured above, Rqc2 (yellow) binds tRNAs (blue and teal), which add amino acids (bright sot in the middle) to a partially-made protein (green). The complex binds the ribosome (white). A truncated protein with a seemingly random sequence of alanines and threonines probably doesn’t work properly, and that tail could be a code that signals for the malformed protein to be destroyed.

Thanks to Kebmodee for bringing this to the attention of the It’s Interesting community.