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Some People's Brains Are Wrinklier Than Others', And Now We Know Why: ScienceAlert

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The folds of the human brain are instantly recognizable. Sinuous ridges and deep ridges give the soft tissue inside the structure of our heads the appearance of a wrinkled walnut.

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

This folding, or gyrification, is crucial to the proper functioning and circuitry of the brain – which is why humans have greater cognitive abilities than monkeys and elephants, whose brains have some folds, and rats and mice, whose smooth-surfaced brains they have none.

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

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

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

Polymicrogyria comes in many forms, with localized or generalized cortical thickening detectable on brain scans.

Mutations in 30 genes and counting have been linked to the condition. But how any one of these genetic errors, alone or together, results in misfolded brain tissue remains unclear. Many cases of PMG also lack an identifiable genetic cause.

It is thought to have something to do with the late migration of cortical brain cells in early development that leads to a disordered cortex. The cortex is the brain’s outermost layer of the brain’s two lobes, a thin layer of gray matter made up of billions of cells.

To investigate further, Gleeson collaborated with researchers at the Institute of Human Genetics and Genome Research in Cairo to access 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 harboring mutations in one gene. This gene encodes a protein that clings to the surface of cells, imaginatively named transmembrane protein 161B (TMEM161B). But nobody knew what it did.

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

However, TMEM161B is from a family of proteins that first appeared, evolutionarily speaking, in sponges – which don’t have a brain.

This intrigued Gleeson and fellow UCSD neuroscientist Lu Wang, who wondered whether the protein could indirectly affect cortical folding by interfering with some basic cellular properties that shape complex tissues.

“Once we identified TMEM161B as the cause, we set out to understand how overfolding occurs,” says Wang, lead author of the study.

Using stem cells derived from skin samples from patients, the researchers generated organoids, tiny tissue replicas that self-assemble in plastic dishes in the same way as body tissues and organs. But the organoids made from patient cells were highly disorganized and showed severed radial glial fibers.

In the developing brain, these progenitor cells—which give rise to neurons and glial cells—generally lie at the apex of the cortex and extend radially downward toward the lower 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, the radial glial fibers in the organoids lost track of how to orient themselves. Other experiments also showed that the cells’ internal cytoskeleton was a mess.

So it appears that, without their own internal scaffolding, radial glial fibers cannot be the scaffolding other cells need to position themselves in the developing brain.

While this discovery is a promising step forward, giving us clues about how the condition develops, 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 scour other datasets for more cases.

“We hope that clinicians and scientists can expand on our results to improve the diagnosis and treatment of patients with brain diseases,” said Gleeson. It’s a long road, but hopeful.

The study was published in PNAS.

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