Scientists Find a Way to Inhibit PAK in Autistic Mice

For the first time, researchers at the Picower Institute for Learning and Memory at MIT have reversed symptoms of mental disability and autism in mice by working with a Fragile X Syndrome, the leading inherited cause of mental disability disorder.

The mice were genetically modified to model this chromosomal syndrome, which is one of the causes of autism. Fragile X Syndrome (FXS) is tied to a mutated X chromosome gene, which causes mild learning disabilities to severe autism. It affects about one in 4,000 males and one in 6,000 females of all races and ethnic groups. The prevalence of autism is about one in 500 or 1 in 166 children and there is no cure for this type of autism or any other types.

"Our study suggests that inhibiting a certain enzyme in the brain could be an effective therapy for countering the debilitating symptoms of FXS in children, and possibly in autistic kids as well," said co-author Mansuo L. Hayashi, a former Picower Institute postdoctoral fellow currently at Merck Research Laboratories in Boston.

A possible target for FXS drug is a key enzyme, which is chemical reaction inducing protein. It is called a p21-activated kinase, or PAK, and it supposedly affects the number, size and shape of connections between the brain and the neurons. Susumu Tonegawa, 1987 Nobel laureate and Picower Professor of Biology and Neuroscience said that inducing PAK's enzymatic activity reversed the structural abnormality found in neuronal connections in mice.

"Strikingly, PAK inhibition also restored electrical communication between neurons in the brains of the FXS mice, correcting their behavioral abnormalities in the process," he said.

He also stated that there are known compounds which inhibit PAK's activity and which are going to be useful in the future development of drugs for treating FXS.

"These are intriguing findings because the expression of the gene that inhibits PAK occurs in the third week after birth, which means that the neuronal abnormalities in the fragile X mouse are reversed after they appear," said Eric Klann, a professor at New York University's Center for Neural Science. "This is very exciting because it suggests that PAK inhibitors could be used for therapeutic purposes to reverse already established mental impairments in fragile X children."

How does it restore neural connections? Looking at the already known structures of the brain, Tonegawa Hayashi, MIT graduate student, and his colleagues analyzed small protrusions called dendritic spines on a branch-like dendrites of one neuron. Usually, this neuron would receive chemical signals from other neurons and then transfer them to the main cell body. The number and shapes of these dendrites are a key to normal functioning. FXS patients tend to have a larger number of these dendritic spines in their brains. Each spine is longer and thinner and in turn, it transmits weaker electric signals. When PAK activity was inhibited, abnormalities in mice spine number as also structure were reversed. Reversing Behavioural Symptoms FXS mice exhibited all of the symptoms FXS patients exhibit: hyperactivity, purposeless, repetitive movements reminiscent of autistic people, attention deficits and difficulty with learning and memory tasks.

"These behavioral abnormalities are ameliorated, partially or fully, by inhibiting the enzymatic activity of PAK," Tonegawa said. "Notably, due to an elegant genetic manipulation method employed by the Picower Institute researchers, PAK inhibition in the FXS mice did not take place until a few weeks after appearance of disease symptoms. This implies that future treatment may still be effective even after symptoms are already pronounced."

"While future studies will be necessary to further characterize the precise molecular nature of the interaction between PAK and FMR1, our findings clearly demonstrate that PAK inhibition can counteract several key cellular and behavioral symptoms of FXS," the authors noted.

Autism is one of the most intriguing disorders known. Patients with this disorder are sometimes able to live normally, but most of the times they have hard time adapting to the society. Reversing these symptoms would give these patients hope of a better life.