New research carried out at the University of California, Los Angeles (UCLA; CA, USA) has uncovered further roles of Rbfox1, a gene known to be linked to the development of autism. The findings were published recently in Neuron and could provide new avenues for treatment targets for the disorder.
“Before we can develop an effective therapy to target a gene, we must first understand how the gene operates in the cell,” commented principal investigator Kelsey Martin (UCLA).
Study coauthor, Daniel Geschwind (UCLA), and colleagues previously linked mutations in Rbfox1 to an increased risk of autism development. By collaborating with UCLA molecular geneticist, Douglas Black (UCLA), they aimed to combine their cell biology approach with sophisticated DNA-sequencing technology to help identify the function of Rbfox1.
“Our results turned up an exciting new set of genetic connections,” commented Black. “We found that where Rbfox1 was located in the cell determined what genes it influenced.”
Rbfox1’s function was compared between the cell nucleus, where it is traditionally considered to have the most impact, and the cytoplasm. Despite previous thinking that the nucleus is the main site of activity for the gene, the team’s experiments indicated that nuclear and cytoplasmic Rbfox1 isoforms regulate distinct neuronal mRNAs.
The genes targeted by Rbfox1 in the cytoplasm were highly enriched with proteins important for healthy development of the brain. The disruption of these genes therefore is thought to result in an increased risk of autism.
“While some experts have hinted at the role of cytoplasmic gene control by Rbfox1 in autism risk, no one has systematically explored it in nerve cells before,” explained Martin.“Our study is the first to discover that dozens of autism risk genes have special functions in the cytoplasm and share common pathways in regulating the brain cells.”
The next aims for the team are to investigate the mechanism by which Rbfox1 controls genes in the cytoplasm in order to ultimately identify new drug targets for the disorder.
“This is a fundamental discovery that poses significant treatment implications,” concluded Geschwind. “Because so many genes are linked to autism risk, identifying common pathways where these genes overlap will greatly simplify our ability to develop new treatments.”
Source: University of California, Los Angeles press release: http://newsroom.ucla.edu/releases/untapped-region-in-brain-cell-offers-goldmine-of-drug-targets-for-new-autism-treatments; Lee J et al. Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-Related Genes. Neuron 89(1), 113–128 (2016).