A new study showed that blocking the activity of hnRNP A1, a protein involved in RNA processing, could disrupt myelin repair in the brain—but may not cause noticeable behavioral changes in mice.
The findings could help clarify the role of RNA-binding proteins in brain health, particularly in diseases involving demyelination such as multiple sclerosis.
In the study, researchers used cuprizone to induce demyelination in mice by damaging the myelin sheath—the protective covering around nerves. After 5 weeks, the chemical was removed to allow recovery. During this phase, the mice were treated with VPC-80051, an inhibitor that blocks hnRNP A1’s splicing activity.
The researchers examined three brain regions: the corpus callosum, the prefrontal cortex, and the hippocampus. Blocking hnRNP A1 altered the levels of key myelin-related proteins, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). The most pronounced changes occurred in the prefrontal cortex, where PLP levels remained suppressed even following recovery.
Despite these molecular changes, the mice showed no clear behavioral deficits. Standard tests of locomotion and memory indicated that VPC-80051–treated mice performed similarly to controls, suggesting that while myelin-related proteins were affected, short-term behavior was preserved.
“Proteins integral to myelination were dysregulated, such as MOG, MAG, MBP, CNP, and PLP, emphasizing the intricate interplay between [RNA-binding proteins] and myelin-related proteins,” said lead study author Caroline Brandão-Teles, of the University of Campinas in Brazil, and colleagues.
Further analysis showed that hnRNP A1 inhibition also affected pathways related to synapses, neurotransmission, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. This indicated that hnRNP A1 could play broader roles in brain function beyond myelin production.
The researchers used nanoLC–MS/MS proteomics to measure protein expression and included behavioral testing. Mice maintained normal weight and showed no distress, and all procedures met ethical standards.
The researchers noted that understanding how hnRNP A1 functions could inform new therapeutic strategies for neurodegenerative conditions. They emphasized the need for long-term studies to evaluate whether behavioral effects might appear later.
The authors reported no conflicts of interest.
Source: Journal of Neurochemistry
