M6A RNA modification profiled in human brain across lifespan
M6A (N6-methyladenosine) is a chemical modification of RNA, which can influence how that RNA is spliced, exported from the nucleus, or translated into protein. In the brain, M6A modification is critical; interfering with the enzymes that add M6A to RNA can disrupt neurogenesis or memory consolidation.
In a recent Nature Neuroscience paper, Andrew Shafik, Peng Jin and colleagues mapped patterns of M6A modification of RNA in human brain across the lifespan. M6A was profiled in five different brain tissues -- frontal cortex, anterior cingulate cortex, caudate, hippocampus, thalamus -- in individuals ranging from age 0 to 71.
Major findings in the paper include widespread regional differences in m6A patterns, especially in genes linked to intellectual disability, autism, neurodevelopmental disorder and seizures. M6A modification was predominantly variable across brain regions rather than across age groups, but age-related m6A changes were most pronounced in the prefrontal cortex.
Microbial solutions for metabolic disorders
You may have heard advertisements for ZBiotics, bacteria engineered to prevent hangovers by supplying extra acetaldehyde dehydrogenase. The idea of using microorganisms to treat a hangover – basically, a temporary metabolic disorder – has gone mainstream. But getting microorganisms to treat permanent (genetic) metabolic disorders may be more difficult.
Judy Fridovich-Keil’s lab reported in Journal of Inherited Metabolic Diseases that a strain of yeast can deliver the ability to metabolize dietary galactose to a rat model of galactosemia. The yeast strain was created through “adaptive evolution” by a San Diego-based company called GutsyBio, which is developing fungal treatments for galactosemia and hereditary fructose intolerance. In this pilot study, the yeast was given to the rats just before the galactose, and the authors didn’t expect the yeast to survive long-term in the mammalian gut.
The idea behind the yeast treatment was to give people living with galactosemia a temporary metabolic safety net. For example, if they wanted to eat a normally forbidden treat at a party, Fridovich-Keil says. How any yeast treatment should be implemented in the clinic or at home still needs to be worked out.
New gene variants causing Van der Woude syndrome identified
A team of researchers has identified a new gene mutated in Van der Woude syndrome, an inherited disorder perturbing the development of the face and mouth. People with Van der Woude syndrome often have a cleft lip or cleft palate, combined with lower lip pits.
Emory geneticists teamed up with clinicians across North America to identify the new gene, called PRKCI (protein kinase C-I). In collaboration with scientists at the University of Washington, they also tested the effects of variants in PRKCI on zebrafish embryos.
The results were published on September 2025 in American Journal of Human Genetics.
The prevalence of Van der Woude syndrome is about 1:35,000 live births. In total, the team identified de novo PRKCI variants in 7 individuals with Van der Woude syndrome or syndromic cleft lip or palate. They found additional PRKCI variants in clinical databases.
“One of the unique things about PRKCI is that there are neurodevelopmental phenotypes in some of the individuals with pathogenic variants in this gene, which is not a phenotype typically associated with Van der Woude syndrome or peridermopathies,” says lead author Elizabeth Leslie-Clarkson, PhD.
Van der Woude syndrome is one of a related set of disorders called peridermopathies arising due to defects of the periderm: a layer of cells that lines the oral cavity and other structures in the developing embryo. More here.
Clues to how ASOs can be optimized in future neurology trials
Cell, August 26, 2025
Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS
Zack McEachin’s collaboration with Jonathan Glass and Emory ALS Center may help explain why a once-promising experimental medication for ALS failed to help patients, despite successfully reaching its intended target in the central nervous system.
The experimental therapy, called BIIB078, was an antisense oligonucleotide or ASO, designed to block the production of toxic RNA and proteins in people with the C9orf72 form of ALS: the most common inherited cause of the disease. A clinical trial of BIIB078 was stopped in 2021 after patients showed no clinical improvement, but the biological responses to the ASO were uneven between patients. Clinical trials of ASOs continue in ALS and several other neurological diseases, so this data can guide the design of future studies.