Study Identifies Mechanism Leading to Cortical Malformation from Brain-only Mutations

Formation of primary cilia, one of cellular organelles, was disrupted in MTOR mutation-carrying neurons and demonstrated that this ciliary disruption was a cause of cortical dyslamination in focal malformations of cortical development (FMCDs), found the Korean research team led by Professor Jeong Ho Lee at the Korea Advanced Institute of Science and Technology (KAIST). The study results are published in Neuron. FMCDs are the most common causes of medically refractory epilepsy in children and are highly associated with intellectual disability, developmental delay, and autism-spectrum disorders. Despite a broad spectrum of cortical abnormalities in FMCDs, the defective migration of neuronal cells is considered a key pathological hallmark.

The research team previously demonstrated that brain-only mutations in the mechanistic target of rapamycin (MTOR) gene causes focal cortical dysplasia, one major form of FMCDs leading to intractable epilepsy in children. However, the molecular mechanisms by which brain-only mutations in MTOR lead to cortical dyslamination and defective neuronal migration in FMCDs remain unclear.

To study the molecular mechanism of brain cortical dyslamination, the research team utilized patients' brain tissues and modeled the MTOR mutation-carrying cell and animal models recapitulating the pathogenesis and symptoms of FMCD patients.

MTOR mutations prevented degradation of the OFD1 protein, one of the negative regulators of ciliary formation. As a result, the OFD1 protein was abnormally accumulated in MTOR mutation-carrying neurons, causing focal cortical dyslamination. By suppressing the expression of the OFD1 protein, the research team was able to rescue the defective formation of primary cilia, leading to the restoration of cortical dyslamination and defective neuronal migration considerably.

Based on these results, the research team is carrying out further research to develop novel therapeutics for patients with FMCDs caused by brain-only mutations.

Source-Eurekalert