Possible Treatment for Brain Disorders

Tuberous Sclerosis is a rare genetic disease that causes the growth of tumors in the brain and other vital organs and may also lead to other conditions such as autism, epilepsy, and cognitive impairment; all of which result from the abnormal generation of neurons.

Tuberous sclerosis is also called tuberous sclerosis complex or TSC, and it is a rare genetic disease that affects multiple organ systems. TSC causes the growth of benign tumors in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. TSC typically affects the central nervous system and results in a combination of symptoms including seizures, developmental delay, behavioral problems, skin abnormalities, and kidney disease.

TSC affects as many as 25,000 to 40,000 individuals in the United States and about 1 to 2 million individuals worldwide. The estimated prevalence of this disease is one in 6,000 newborns, and it occurs in all races and ethnic groups, and in both genders.

TSC derives its name from the characteristic tuber or potato-like nodules in the brain. These growths calcify with age and become hard or sclerotic.

Many TSC patients show evidence of the disorder in the first year of life. However, clinical features can be subtle initially, and many signs and symptoms take years to develop. As a result, TSC can be unrecognized or misdiagnosed for years.

TSC is caused by defects, or mutations, on two genes-TSC1 and TSC2. Only one of the genes needs to be affected for TSC to be present. The TSC1 gene, discovered in 1997, is on chromosome 9 and produces a protein called Hamartin. The TSC2 gene, discovered in 1993, is on chromosome 16 and produces the protein Tuberin. These proteins combine to form a complex that suppresses cell growth by preventing activation of a master control protein called mTOR. Loss of regulation of mTOR occurs in cells lacking either Hamartin or Tuberin, and this leads to abnormal differentiation and development, and to the generation of enlarged cells, as are seen in TSC brain lesions.

Since Tuberous Sclerosis affect stem cell activity, scientists at Clemson University are examining how neurons are formed from neural stem cells and this research is vital to providing a treatment to Tuberous Sclerosis, which affects how neurons are formed in the brain.

David M Feliciano, assistant professor of biological sciences at Clemson University, said: “Current medicine is directed at inhibiting the mammalian target of rapamycin (mTOR), a common feature within these tumors that have abnormally high activity. However, current treatments have severe side effects, like due to mTOR’s many functions and playing an important role in cell survival, growth and migration.”

mTOR pathway

Feliciano continued: “Neural stem cells generate the primary communicating cells of the brain called neurons through the process of neurogenesis, yet how this is orchestrated is unknown.”

Neural stem cells lie at the very heart of brain development and repair, and alterations in the ability of these cells to self-renew and differentiate can have profound consequences for brain function at any stage of life, according to researchers.

In order to further elucidate the regulation of neurogenesis, Feliciano and his team delivered small pieces of DNA into the neural stem cells of the new-born mice. The team used electroporation to introduce the DNA into the mouse cells, and these small pieces of DNA allowed Feliciano’s team to express and control specific components of the mTOR pathway.

By using these tools, Feliciano and others showed that Increasing the activity of the mTOR pathway cause the neural stem cells to make more neurons at the expense of self-renewal. Increasing mTOR activity caused upregulation of 4E-BP2. 4E-BP2, also known as Eukaryotic translation initiation factor 4E-binding protein 2, binds to a component of the protein synthesis machinery and inhibits its function. Mice that lack functional EIF4EBP2 exhibit autism-like symptoms, including poor social interaction, altered communication and repetitive behaviors.

This work suggests that 4E-BP2 might be a new target for the treatment of TSC and that targeting this protein might cause fewer side effects than targeting mTOR. Future experiments hope to identify those proteins that are made due to the activation of this pathway in neural tissues.