Some people’s brains are wrinklier than others, and now we know why: ScienceAlert

The folds of the human brain are immediately recognizable. Serpentine ridges and deep furrows give the squishy tissue inside our heads structure and the appearance of a wrinkled walnut.

Into ridges called gyri and crevices called sulci, the outermost layer of brain tissue is folded so that masses of it can be squeezed into the skull, and it is here, on the brain’s wrinkled surface, that memory, thinking, learning and reasoning occur. .

This folding, or gyrification, is essential for proper brain function and circuitry – and is said to be why humans have greater cognitive abilities than monkeys and elephants, whose brains have some folds, and rats and mice, whose smooth-surfaced brains have none .

Now a team of researchers has discovered why some people have more brain folds than others, in a condition that affects normal brain development called polymicrogyria (PMG).

In polymicrogyria, too many gyri are stacked on top of each other, resulting in an abnormally thick cortex and leading to a wide range of problems such as neurodevelopmental delays, intellectual disability, speech difficulties and epileptic seizures.

“Until recently, most hospitals treating patients with this condition did not test for genetic causes,” explains University of California San Diego (UCSD) neuroscientist Joseph Gleeson, one of the researchers behind the new study.

Polymicrogyria comes in many forms, with localized or widespread cortical thickening that can be detected on brain scans.

Mutations in 30 genes and counting have been associated with the condition. But how any of these genetic errors, alone or in tandem, result in overfolded brain tissue remains unclear. Many cases of PMG also lack an identifiable genetic cause.

It is thought to have something to do with the delayed migration of brain cells in the cerebral cortex during early development leading to a disrupted cortex. The cortex is the outermost layer of the brain’s bilobed cerebrum, a thin sheet of gray matter made up of billions of cells.

To investigate further, Gleeson collaborated with researchers at the Human Genetics and Genome Research Institute in Cairo to draw on a database of nearly 10,000 Middle Eastern families affected by some form of pediatric brain disease.

They found four families with an almost identical form of PMG, all with mutations in one gene. That gene codes for a protein that clings to the surface of cells, with the imaginative name transmembrane protein 161B (TMEM161B). But no one knew what it did.

In subsequent experiments, Gleeson and colleagues showed that TMEM161B is found in most fetal brain cell types: in stem cells that grow into specialized neurons, in mature neurons that excite or inhibit their neighbors, and in glial cells that support and protect neurons in various ways.

However, TMEM161B is from a family of proteins that first appeared, evolutionarily speaking, in sponges – which have no brain.

This puzzled Gleeson and fellow UCSD neuroscientist Lu Wang who wondered if the protein might indirectly affect cortical folding by interfering with some basic cellular properties that give shape to complex tissues.

“Once we identified TMEM161B as the cause, we set out to understand how excessive folding occurs,” says Wang, the study’s lead author.

Using stem cells from the patient’s skin samples, the researchers generated organoids, tiny tissue copies that self-organize in plastic dishes like body tissues and organs do. But the organoids made from patient cells were highly disorganized and showed disrupted radial glial fibers.

In the developing brain, these progenitor cells—which give rise to neurons and glia—usually position themselves on top of the cortex and extend radially downward toward the bottom layer of cortical tissue. This creates a scaffolding system that supports the migration of other newly formed cells as the cortex expands.

But without TMEM161B, radial glial fibers in the organoids had lost their sense of which way to orient. Further experiments also showed that the cells’ internal cytoskeleton was a mess.

So it appears that without its own internal scaffolding, radial glial fibers cannot provide the scaffolding that other cells need to find their way into position in the developing brain.

Although this discovery is a promising step forward, and gives us clues to how the condition plays out, it may only be relevant to a small or as yet unknown fraction of PMG cases.

Much more research is needed to deepen our understanding of how many people with PMG are affected by mutations in TMEM161B – but now researchers know what to look for, they can trawl other datasets looking for more cases.

“We hope that doctors and researchers can extend our results to improve the diagnosis and care of patients with brain disease,” says Gleeson. It’s a long road, but a hopeful one.

The study is published in PNAS.

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