Targeting gene network to treat autism and intellectual disability

Targeting gene network to treat autism and intellectual disability

A mutated gene found in people with intellectual disabilities that could be targeted for treatment has been identified by an international team.

The gene, USP9X, regulates a network of genes underlying Intellectual Disability (ID) and Autism Spectrum Disorder (ASD).

The senior author author said focussing on the network, rather than individual genes, could lead to therapy developments for a range of neurological disorders. "Treating ID and ASD one gene at a time is not feasible, as more than 1000 genes have been implicated in the conditions," the senior author said.

"Research is switching to identifying networks in which multiple genes function in common pathways, such as USP9X. "USP9X regulates a family of proteins that control how nerves communicate and share information. By targeting this network, there is a possibility that treatments could be developed that will help a wide range of patients."

Mice lacking the USP9X gene were used to study the function of this factor, as well as its interacting partners. Mutations in USP9X have also been implicated in Parkinson's and Alzheimer's diseases.

Usp9X phosphorylation enhances ANK3 gene encoding ankyrin-G interaction, decreases ankyrin-G polyubiquitination, and stabilizes ankyrin-G to maintain dendritic spine development.

In forebrain-specific Usp9X knockout mice (Usp9X –/Y), ankyrin-G as well as multiple ankyrin-repeat domain (ANKRD)-containing proteins are transiently reduced at 2 but recovered at 12 weeks postnatally. However, reduced cortical spine density in knockouts persists into adulthood.

Usp9X –/Y mice display increase of ankyrin-G ubiquitination and aggregation and hyperactivity. USP9X mutations in patients with intellectual disability and autism ablate its catalytic activity or ankyrin-G interaction. 

The research showed a critical two-week period following birth where development of USP9X is crucial to normal brain function. "This represents a window of opportunity for therapeutical intervention," the senior author said.

"It is possible that this model will help test interventions in mice as a step towards developing new therapeutic approaches for patients."