The folds of the human brain are immediately recognizable. The snaking ridges and deep furrows give the spongy tissue inside our head structure and the appearance of a wrinkled nut.
In peaks called gyri and fissures called sulci, the outermost layer of brain tissue is folded so that oars of it can be pressed into the skull, and it is here, on the wrinkled surface of the brain, that memory, thought, learning and reasoning occur. .
This folding, or gyrification, is crucial for the proper functioning and circuitry of the brain – and is said to be why humans have greater cognitive abilities than monkeys and elephants, whose brains have folds, and rats and mice, whose smooth-surfaced brains do not.
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, too many gyri are piled on top of each other resulting in an abnormally thick cortex and leading to a wide range of problems such as neurodevelopmental delay, intellectual disability, speech difficulties and seizures of epilepsy.
“Until recently, most hospitals treating patients with this disease did not test for genetic causes,” says Joseph Gleeson, a neuroscientist at the University of California San Diego (UCSD), one of the researchers at the origin of the new study.
Polymicrogyria presents in many forms, with localized or generalized cortical thickening detectable on brain scans.
Mutations in 30 genes and counts have been associated with the disease. But how any of these genetic errors, alone or in tandem, results in overbent brain tissue remains unclear. Many cases of PMG also have no 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 outermost layer of the brain’s two-lobed brain, a thin sheet of gray matter made up of billions of cells.
To further his research, Gleeson collaborated with researchers at the Genetics and Human Genome Research Institute in Cairo to tap into a database of nearly 10,000 Middle Eastern families affected by some form of brain disease. pediatric.
They found four families with an almost identical form of PMG, all carrying mutations in one gene. This gene codes for a protein that latches onto the surface of cells, with the imaginative name transmembrane protein 161B (TMEM161B). But no one 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 develop into specialized neurons, in mature neurons that excite or inhibit their neighbors, and in cells glial cells that support and protect neurons in various ways.
However, TMEM161B belongs to a family of proteins that first appeared, evolutionarily, in sponges – which lack brains.
This intrigued Gleeson and fellow UCSD neuroscientist Lu Wang, who wondered if the protein could indirectly affect cortical folding by meddling with some basic cellular properties that shape 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 derived from patient skin samples, the researchers generated organoids, tiny replicas of tissue that self-organize in plastic dishes like body tissues and organs do. But the organoids made from patient cells were very disorganized and showed disrupted radial glial fibers.
In the developing brain, these progenitor cells – which give rise to neurons and glia – typically position themselves at the top of the cortex and extend radially downward to the lower layer of cortical tissue. This creates a scaffolding system that supports the migration of other newly formed cells as the cortex grows.
But without TMEM161B, the radial glial fibers of the organoids had lost their sense of how to orient themselves. Other experiments also showed that the internal cytoskeleton of cells was in disorder.
So it seems that without their own internal scaffolding, the radial glial fibers cannot be the scaffolding that other cells need to find their way into the developing brain.
While this finding is a promising step forward, giving us clues about the course of the disease, it may only be relevant to a small or still unknown fraction of PMG cases.
Much more research is needed to flesh out 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 research. more cases.
“We hope physicians and scientists can expand our findings to improve the diagnosis and care of patients with brain diseases,” says Gleeson. It’s a long road but full of hope.
The study was published in PNAS.