As originally reported in MSU Today; in new experiments on mice, researchers looked into how the TS gene is related to autism. Tuberous sclerosis is a rare disorder known for it’s characteristic tumors and behavioural effects. The disorder is highly correlated with both autism, about half of patients, and seizures, at 90% overlap. This experiment helped the researchers understand the logistics of the gene mutation: not only what genes are mutated but what the effect of the mutation is. In this case, they found the mutated genes cause the pathways to fail to properly regulate the MTOR protein, which they have discovered is crucial to managing cell production. Consequentially, cell growth is unregulated, causing the characteristic tumors.
What is Tuberous Sclerosis?
Tuberous sclerosis is a rare genetic disorder that causes non-cancerous tumors across the body and its many organs. Symptoms often also include skin discolouration, thickness, or growths; lung, kidney, heart, or eye issues; and behavioural effects such as communication issues, developmental delays, anger, hyperactivity, and unhealthy emotional regulation.
The disorder is caused by a mutation in either of two genes, which are crucial to a pathway that balances cell growth. Because of the mutation, the cell growth is not properly regulated, so they tend to divide excessively. These extra cells cause the lesions and tumors. The new research is interesting in the cognitive effects due to the cell changes in the brain- the reason the disease is highly correlated with autism and seizures. They dove into the specifics of the malfunctioning brain cells.
The New Research
Nature communication’s research is more specific: they have found the specific ingredient causing improper cell growth regulation: there is an excess of the ‘MTOR’ protein in the cells. The disorder’s mutation causes the pathway to fail to effectively turn off this protein. The excess of this protein damages the development and functioning of these brain cells, thus disrupting brain activity. When this MTOR protein is active in brain cells when it shouldn’t be, the imbalanced brain activity can cause autism and seizures.
The researchers used mice which lacked the TCS1 gene, one of the two gene mutations responsible for tuberous sclerosis. They found the mice with the TCS1 mutation had the protein irregularly distributed, with some cells with excessive MTOR. While they had been aware the mutation effected this pathway, they had not been aware of how important this specific protein is.
Daniel Vogt, professor and author at MSU College of Human Medicine, explained that the realization of the importance of the MTOR protein was very surprising for the medical field, who still do not entirely understand its full role. They did know this pathway is associated is with other disorders that similarly are correlated to autism.
A Solution
The knowledge of MTOR’s role gave the scientists insight into an important potential remedy: if too much of the MTOR protein is damaging brain functioning, block the MTOR protein.
The researchers gave the animals the drug ‘rapamycin’, which blocks the protein. The drug is repurposed for this use- already it is sold “under the tradename Sirolimus, which is used to prevent organ transplant rejection and treat skin lesions.” The researchers report after just five days, the mice with the mutation experiencing altered brain activity could have this reversed: and the cells could revert to their healthy functioning.This makes the scientists believe that the pathways damaged by this mutation could have their functioning resolved by treatment. Basically, the pathways are mostly repairable and once this is done, the cell regulation is healthier.
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Vogt explained that this discovery addresses not only tuberous sclerosis, but the gives molecular insights into the causes of both epliepsy and autism. This is a good insight into one of many positive effects of rare disease research: even if the TS is rare, understanding it can lead to a web of understanding about other diseases plaguing the medical world.
