The study identifies the cause of the excessive folding

Brain wrinkle

Image: The intricate surface folding of the human brain allows the organ to compress 2.6 square feet of cerebral cortex tissue into the skull.
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Credit: California Institute for Regenerative Medicine

The outermost layer of the human brain or cerebral cortex, which has its characteristic dents and fissures (those distinctive bumps and grooves), controls cognitive and executive function, from conscious thinking to speech to emotional control.

Made up of more than 10 billion cells and 100 trillion plus connections, the cerebral cortex is a layer of gray matter just five millimeters thick—just under three-quarters stacked.

Most large-brained animals exhibit cortical folding, which allows a very large area of ​​cerebral cortical tissue (about 2.6 square feet) to be compressed within the confines of the skull. The greater the cortical folding, the more advanced and complex the cognitive functions of the species. Lower species such as mice and rats have smaller brains and smooth surfaces. Higher-order species such as elephants, porpoises, and monkeys show different degrees of rotation, or folding, of the cerebral cortex. Humans have among the most wrinkled brains, which is considered an indicator of advanced evolution.

However, in some humans, increased folding of the cerebral cortex is not associated with greater cognitive abilities, but rather the opposite and is associated with neurodevelopmental delay, intellectual disability and epileptic seizures. The genes that control this folding are mostly unknown.

Writing in the January 16, 2023 issue of PNASResearchers at the University of California San Diego School of Medicine and the Rady Children’s Institute for Genomic Medicine describe new findings that deepen understanding of human sweating.

Led by the study’s senior author Joseph Gleason, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and Director of Neuroscience Research at the Rady Children’s Institute for Genomic Medicine, an international consortium of researchers called the Neurogenetics Consortium performed a genomic analysis of nearly 10,000 families with pediatric brain disease over the course of 10 years to search for new causes of the disease.

“Out of our group, we found four families with a condition called polymicrogyria, which means they have a very large number of highly congested gyroscopes,” Gleason said. Until recently, most hospitals treating patients with this condition did not test for genetic causes. The consortium was able to analyze all four families together, which helped us discover a cause for this condition.”

Specifically, all four families showed mutations in a gene called Transembrane Protein 161B (TMEM161B), which produces a previously unknown protein on cell surfaces.

“Once we identified TMEM161B as the cause, we set out to understand how hyperfolding occurs,” said first author Lu Wang, PhD, a postdoctoral fellow in Gleeson’s lab. “We discovered that the protein controls cellular skeleton and polarity, and these control folding.”

Using stem cells derived from patient skin samples, and engineered mice, researchers have identified defects in neuronal interactions early in embryonic development.

“We found that the gene is both necessary and sufficient for the cytoskeletal changes required for how neurons interact with each other,” Wang said. “It was interesting that the gene first appeared in evolution in sponges, which don’t even have a brain, so clearly the protein must It has other functions, and here we found a crucial role in regulating the number of folds in the human brain.”

The study authors stress that genetic discovery studies are important because they identify the causes of human disease, but that these discoveries can take many years to develop into new treatments.

“We hope that clinicians and scientists can expand on our findings to improve diagnosis and care for patients with brain diseases,” Gleason said.

Co-authors are: Caleb Hefner and Stephen A. Murray, The Jackson Laboratory, Bar Harbor, Minnesota; Keng loi Vonga, David Sieverta, and Swapnil Mittala, Rady Children’s Institute for Genomic Medicine; Chelsea Barrows, Sangmun Lee, Ishani Jump, UC San Diego, and Rady Children’s Institute for Genomic Medicine; Yu Jin-ha, Yonsei University, Seoul; Pablo Lara Gonzalez, University of California, Irvine; Denise van der Meer, Nadine Parker and Ollie A. Andreessen, University of Oslo; Robert Loughnan, University of California, San Diego; Mahmoud Youssef Issa and Maha Zaki, National Research Center, Cairo; Anders Dale, University of California San Diego and University of Oslo; and William B. Dobbins, University of Minnesota.

YouTube video: https://youtu.be/aLvJr6eJnl8

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