Research has revealed some mechanistic underpinnings of syndromic forms of autism spectrum disorder (ASD)—those that have a defined pattern of abnormalities and are likely to have a known genetic cause. Now, through the analysis of postmortem brain tissue from ASD patients, a new study revealed that certain people with ASD have a cellular abnormality that impairs production of myelin, a fatty substance that creates an insulative sheath around nerve fibers in the brain. And, that this impairment of “myelination” may be involved in the disorder.

The research is published in Nature Neuroscience in a paper titled, “A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder.

“This could be a sea change in our understanding of what causes people to suffer this serious brain disorder,” said Daniel R. Weinberger, MD, CEO and director of the Lieber Institute for Brain Development (LIBD) at the Johns Hopkins Medical Campus. “We’re actively testing in experimental models drugs that might correct this abnormality.”

Brady Maher, PhD, LIBD’s lead investigator on the study, said that in trying to understand the root causes of ASD, most researchers have focused on potential problems with neurons, the principal cells of the brain. But he said that this new study indicates that problems with a supporting cell that is critical for insulating the nerve fibers may be a previously underappreciated mechanism.

The team’s goal was two-fold. The first goal was to “address several fundamental questions about the relevance of animal models for the study of human ASD” and the second “to identify a common pathophysiology that bridges the ASD spectrum.”

To do this, the team looked to their previous research on Pitt–Hopkins syndrome, a rare neurodevelopmental disorder that is a syndromic form of ASD, caused by mutations in the TCF4 gene.

They performed transcriptomic analyses of seven independent mouse models covering three syndromic forms of ASD generated across five laboratories. Then, they assessed dysregulated genes and their pathways in human postmortem brain from people with ASD and neurotypical controls.

These cross-species analyses converged on the identification of a genetic abnormality that disrupts the function of cells that control myelin production called oligodendrocytes (OL).

“Myelination is essential to healthy brain development, it’s a process that begins just before birth and continues throughout the lifespan. If impaired, it leads to abnormal brain development that likely results in communication and behavior challenges associated with ASD,” Maher said.

The researchers then explored other ASD mouse models caused by different mutations associated with autism and found consistent evidence for abnormalities in oligodendrocytes. Remarkably, in a collection of donated brain tissue from deceased people with ASD who did not suffer from Pitt–Hopkins syndrome but had more common forms of ASD, they observed the same abnormality: problems with OL cells that impair myelin production, something that is not found in brains of non-ASD patients.

“It appears that in many people who suffer from ASD, their OL cells are not maturing sufficiently or functioning properly,” Maher said. “This suggests they are not producing enough myelin insulation for their neurons, which could profoundly disrupt brain development and electrical communication in the brain.”

He noted that previous studies have shown that people with ASD can exhibit a decrease in myelin thickness in certain regions of the brain. He said recent evidence, in addition to his own, suggests that people with ASD have fewer OL cells. But Maher said that previous research had not connected the dots—that there appears to be an underlying biological process in people with ASD limiting the capacity of OL cells to produce the myelin brains need for proper development. And that deficiency could be a key source of the neurological problems seen in people with this disorder. Also, he said given the different factors that influence myelin production in OL cells, the defects in myelination could vary considerably across individual cases of ASD, corresponding to the variation in the severity of symptoms across the autism spectrum.

Maher said he and his colleagues at the Lieber Institute are now testing compounds that may have the capacity to boost myelination in the brain. “Because myelination is a lifelong process it provides a unique therapeutic opportunity that we can tap into throughout the lifespan. Along these lines, we are eager to see whether enhancing myelination in these mice can improve their ASD-associated behaviors,” he said. “Promising candidates could then be considered for clinical studies.”

 

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