Mechanism leading to cortical malformation from brain-only mutations identified

July 3, 2018, The Korea Advanced Institute of Science and Technology (KAIST)
The disrupted formation of primary cilia in brain tissues of FMCD mouse models and patients with FMCDs caused by brain somatic mutations in MTOR. Credit: KAIST

Focal malformations of cortical development (FMCDs) are a heterogeneous group of brain cortical abnormalities. These conditions are the most common causes of 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.

A Korean research team led by Professor Jeong Ho Lee at the Korea Advanced Institute of Science and Technology (KAIST) has recently investigated the molecular mechanism of defective neuronal migration in FMCDs. Their research results were published online in Neuron on June 21, 2018.

The research team previously demonstrated that brain-only 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. By performing comprehensive molecular genetic experiments, they found that the formation of , one of cellular organelles, was disrupted in MTOR mutation-carrying neurons and demonstrated that this ciliary disruption was a cause of cortical dyslamination in FMCDs.

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 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.

Explore further: Mutations taking place only in the brain identified as the cause of intractable epilepsy

More information: Sang Min Park et al, Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination, Neuron (2018). DOI: 10.1016/j.neuron.2018.05.039

Related Stories

Mutations taking place only in the brain identified as the cause of intractable epilepsy

March 24, 2015
Epilepsy is a brain disorder that afflicts more than 50 million people worldwide. Many epilepsy patients can control their symptoms through medication, but about 30% suffer from intractable epilepsy and are unable to manage ...

Mechanism underlying malformation associated with severe epilepsy is revealed

May 17, 2018
One of the most frequent causes of drug-resistant epilepsy, considered a difficult disease to control, is a brain malformation known as focal cortical dysplasia. Patients with this problem present with discreet disorganization ...

Cause of cortical malformations targeted by researchers

September 22, 2016
Cortical malformations are a major cause of epileptic seizures and are a hallmark feature of many neurodevelopmental disorders. Expanding upon its recently-published model of cortical malformations, a Yale team lead by neuroscientist ...

Scientists find cancer-causing virus in the brain, potential connection to epilepsy

January 24, 2013
Researchers at Shriner's Hospital Pediatric Research Center at the Temple University School of Medicine, and the University of Pennsylvania have evidence linking the human papillomavirus 16 (HPV16) – the most common cause ...

The extent of neuronal loss in the brain during MS

May 10, 2017
A study by researchers from Queen Mary University of London establishes for the first time the extent of neuronal loss in the brain of a person with MS over their life, and finds that demyelination may not be as good an indicator ...

Patient stem cells used to make dementia-in-a-dish; help identify new treatment strategy

December 31, 2014
Belgian researchers have identified a new strategy for treating an inherited form of dementia after attempting to turn stem cells derived from patients into the neurons most affected by the disease. In patient-derived stem ...

Recommended for you

The importins of anxiety

December 11, 2018
According to some estimates, up to one in three people around the world may experience severe anxiety in their lifetime. In a study described today in Cell Reports, researchers at the Weizmann Institute of Science have revealed ...

Neurons in the brain work as a team to guide movement of arms, hands

December 11, 2018
The apparent simplicity of picking up a cup of coffee or turning a doorknob belies the complex sequence of calculations and processes that the brain must undergo to identify the location of an item in space, move the arm ...

How returning to a prior context briefly heightens memory recall

December 11, 2018
Whether it's the pleasant experience of returning to one's childhood home over the holidays or the unease of revisiting a site that proved unpleasant, we often find that when we return to a context where an episode first ...

The richer the reward, the faster you'll likely move to reach it, study shows

December 11, 2018
If you are wondering how long you personally are willing to stand in line to buy that hot new holiday gift, scientists at Johns Hopkins Medicine say the answer may be found in the biological rules governing how animals typically ...

Using neurofeedback to prevent PTSD in soldiers

December 11, 2018
A team of researchers from Israel, the U.S. and the U.K. has found that using neurofeedback could prevent soldiers from experiencing PTSD after engaging in emotionally difficult situations. In their paper published in the ...

Study: Age, race differences determine risk of stroke in women and men

December 11, 2018
A new study found that, between the ages of 45 and 74 years, white women were less likely to have a stroke than white men, but at age 75 and older, there was no difference in stroke risk between white women and men. In contrast, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.