Genetics

dna-parasite-now-plays-key-role-in-making-critical-nerve-cell-protein

DNA parasite now plays key role in making critical nerve cell protein

Biology, evolution, Genetics, Genomics, myelin, neurobiology, Science, transposons / /

Domesticated viruses —

An RNA has been adopted to help the production of myelin, a key nerve protein.

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Graphic depiction of a nerve cell with a myelin coated axon.

Human brains (and the brains of other vertebrates) are able to process information faster because of myelin, a fatty substance that forms a protective sheath over the axons of our nerve cells and speeds up their impulses. How did our neurons evolve myelin sheaths? Part of the answer—which was unknown until now—almost sounds like science fiction.

Led by scientists from Altos Labs-Cambridge Institute of Science, a team of researchers has uncovered a bit of the gnarly past of how myelin ended up covering vertebrate neurons: a molecular parasite has been messing with our genes. Sequences derived from an ancient virus help regulate a gene that encodes a component of myelin, helping explain why vertebrates have an edge when it comes to their brains.

Prehistoric infection

Myelin is a fatty material produced by oligodendrocyte cells in the central nervous system and Schwann cells in the peripheral nervous system. Its insulating properties allow neurons to zap impulses to one another at faster speeds and greater lengths. Our brains can be complex in part because myelin enables longer, narrower axons, which means more nerves can be stacked together.

The un-myelinated brain cells of many invertebrates often need to rely on wider—and therefore fewer—axons for impulse conduction. Rapid impulse conduction makes quicker reactions possible, whether that means fleeing danger or capturing prey.

So, how do we make myelin? A key player in its production appears to be a type of molecular parasite called a retrotransposon.

Like other transposons, retrotransposons can move to new locations in the genome through an RNA intermediate. However, most retrotransposons in our genome have picked up too many mutations to move about anymore.

RNLTR12-int is a retrotransposon that is thought to have originally entered our ancestors’ genome as a virus. Rat genomes now have over 100 copies of the retrotransposon.

An RNA made by RNLTR12-int helps produce myelin by binding to a transcription factor or a protein that regulates the activity of other genes. The RNA/protein combination binds to DNA near the gene for myelin basic protein, or MBP, a major component of myelin.

“MBP is essential for the membrane growth and compression of [central nervous system] myelin,” the researchers said in a study recently published in Cell.

Technical knockout

To find out whether RNLTR12-int really was behind the regulation of MBP and, therefore, myelin production, the research team had to knock its level down and see if myelination still happened. They first experimented on rat brains before moving on to zebrafish and frogs.

When they inhibited RNLTR12-int, the results were drastic. In the central nervous system, genetically edited rats produced 98 percent less MBP than those where the gene was left unedited. The absence of RNLTR12-int also caused the oligodendrocytes that produce myelin to develop much simpler structures than they would normally form. When RNLTR12-int was knocked out in the peripheral nervous system, it reduced myelin produced by Schwann cells.

The researchers used a SOX10 antibody to show that SOX10 bound to the RNLTR12-int transcript in vivo. This was an important result, since there are lots of non-coding RNAs made by cells, and it wasn’t clear whether any RNA would work or if it was specific to RNLTR12-int.

Do these results hold up in other jawed vertebrates? Using CRISPR-CAS9 to perform knockout tests with retrotransposons related to RNLTR12-int in frogs and zebrafish showed similar results.

Myelination has enriched the vertebrate brain so it can work like never before. This is why the term “brain food” is literal. Healthy fats are so important for our brains; they help form myelin since it is a fatty acid. Think about that next time you’re pulling an all-nighter while reaching for a handful of nuts.

Cell, 2024. DOI: 10.1016/j.cell.2024.01.011

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surprising-link-found-between-niacin-and-risk-of-heart-attack-and-stroke

Surprising link found between niacin and risk of heart attack and stroke

cardiovascular disease, cleveland clinic, Genetics, health, heart attack, inflammation, metabolites, niacin, Science, stroke, vitamin b3 / /

Unexpected —

Breakdown products of niacin, aka Vitamin B3, may spur vascular inflammation.

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A shopper looks at a meat display on June 20, 2022, at the Market 32 Supermarket in South Burlington, Vermont. Niacin can be found in foods such as red meat, poultry, fish, fortified cereals and breads, brown rice, nuts, legumes, and bananas.

Enlarge / A shopper looks at a meat display on June 20, 2022, at the Market 32 Supermarket in South Burlington, Vermont. Niacin can be found in foods such as red meat, poultry, fish, fortified cereals and breads, brown rice, nuts, legumes, and bananas.

In the early 20th century, the deadliest nutrient-related disease in US history ravaged the American South. Pellagra, a disease caused by a deficiency in niacin and/or tryptophan, is marked by the four “D’s”: diarrhea, dermatitis that leads to gruesome skin plaques, dementia, and death. At its peak during the Great Depression, pellagra killed nearly 7,000 Southerners a year. Between 1906 and 1940, researchers estimate that the epidemic struck roughly 3 million Americans, killing around 100,000.

The deadly epidemic led to voluntary—and eventually mandatory—fortification of wheat and other cereals with niacin (aka Vitamin B3). By the middle of the century, pellagra nearly vanished from the US. But, decades later, the public health triumph may be backfiring. With Americans’ diets more reliant than ever on processed, niacin-fortified foods, the average niacin intake in the US is now nearing what’s considered the tolerable upper limit of the nutrient, according to a federal health survey. And an extensive study recently published in Nature Medicine suggests that those excess amounts of niacin may be exacerbating cardiovascular disease, increasing risks of heart attacks, strokes, and death.

The study, led by Stanley Hazen, chair of Cardiovascular and Metabolic Sciences at Cleveland Clinic’s Lerner Research Institute, connected high blood levels of a breakdown product of niacin—and to a lesser extent, tryptophan—to an elevated risk of major adverse cardiovascular events (MACE). And this elevated risk appears to be independent of known risk factors for those events, such as high cholesterol.

“What’s exciting about these results is that this pathway appears to be a previously unrecognized yet significant contributor to the development of cardiovascular disease,” Hazen said in an announcement of the study. It can be measured, he added, and one day could be a new avenue for treatment and prevention.

Metabolite fishing

Hazen and his colleagues didn’t start out suspecting niacin could be a culprit in cardiovascular disease. They arrived at that point after fishing through patients’ blood plasma. The researchers were carefully inventorying metabolites in the fasting plasma of 1,162 patients who had been evaluated for cardiovascular disease. They were looking for anything that might be linked to a heightened risk of heart attack, stroke, or death in a three-year period that couldn’t entirely be explained by other risk factors. Despite advances in identifying and treating cardiovascular disease, researchers have noted that some patients continue to be at risk of serious cardiovascular events despite having their traditional risk factors treated and controlled. Hazen and his colleagues wanted to know why.

The metabolomic trawling came up with an unknown metabolite (signature C7H9O2N2) that was significantly linked to having a MACE in the three-year period. People who had higher levels of this metabolite circulating in their systems were within the top 75th percentile for relative MACE risk in the cohort. Further work identified the metabolite as actually being two related molecules: 2PY (N1-methyl-2-pyridone-5-carboxamide) and 4PY (N1-methyl-4-pyridone -3-carboxamide)—both the final breakdown products of niacin.

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