Researchers at Baylor College of Medicine have developed a potential new approach to autism treatment. Autism affects 1 in 59 children in the United States. In specific cases, autism is caused by a PTEN gene mutation. Phosphatase and tensin homolog (PTEN) is a protein that, in humans, prevents cells from growing and dividing too rapidly.
Currently, there is not an effective treatment for children with this form of autism. Signs of mutated PTEN include macrocephaly (abnormally large skull), epilepsy and intellectual disabilities. A new study by researchers at Baylor offers a new approach.
They discovered that a previously unexplored pathway goes awry in the brains of PTEN-deficient mice, and the restoration of it reverses their neurophysiological and behavioral abnormalities. Even better than discovering this, the researchers were able to treat the symptoms associated with PTEN-deficiency with a new therapeutic strategy they developed.
First author Chien-Ju Chen, a graduate student in the lab of corresponding author Dr. Mauro Costa-Mattioli, said:
PTEN is associated with the mTOR signaling pathway, which includes two distinct molecular complexes — mTORC1 and mTORC2 — each one regulating different cellular functions
The researchers worked with mice that were genetically engineered to lack PTEN, specifically in their neurons or nerve cells in the brain. These mice suffered from macrocephaly, seizures, alterations in social behavior, shorter lifespans, and memory problems similar to children affected by the same autism disorders.
The researchers independently suppressed mTORC1 and mTORC2 using molecular genetics techniques to determine how individual silencing of these complexes affected neurological alterations. They ended up being quite surprised by the results because they went against the traditional views.
Costa-Mattioli said:
We found that genetically silencing the mTORC1 complex in PTEN-deficiency mice only resulted in restoration of the size of the brain. It did not affect survival, the behavioral alterations or even the number of seizures. Unexpectedly, genetically silencing mTORC2 complex activity resulted in prolonged lifespan, suppressed seizures, rescue of long-term memory and reduced autism spectrum disorder-like behaviors.
No drug can specifically inhibit mTORC2. The researchers developed a special molecule, antisense oligonucleotide, which silences the activity of mTORC2 by preventing synthesis of one of its defining components.
“Amazingly, when we administered a single injection of the antisense oligonucleotide, we were able to reverse the abnormal behaviors and reduce seizures in Pten-deficient mice,” said Chen.
These findings are an important discovery because most research up to this point has been focused on developing drugs for mTORC1. What the team discovered is that modulating mTORC2 activity is a promising therapeutic approach to PTEN deficiency and that mTORC2 is the main driver of behavioral and neurological alterations.
The researchers have said this discovery has opened the door to further investigation of other neurological disorders including epilepsy, tuberous sclerosis, Alzheimer’s and Fragile X syndrome. Hopefully, they will be able to determine if mTORC2 is the main complex associated with these disorders as well.
