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Untapped Brain-cell Region Offers Goldmine of Drug Targets for Autism Treatments

  Drug Targets for Autism Treatments

The gene Rbfox1 in a cell’s cytoplasm.
Image: Courtesy of Dr. Kelsey C. Martin

UCLA scientists have discovered that an overlooked region in brain cells houses a motherlode of mutated genes previously tied to autism. The finding could provide fresh drug targets and lead to new therapies for the disorder.

“Our discovery will shed new light on how genetic mutations lead to autism,” says Kelsey C. Martin, MD, PhD, professor of biological chemistry and psychiatry and biobehavioral sciences and interim dean of the David Geffen School of Medicine at UCLA. “Before we can develop an effective therapy to target a gene, we must first understand how the gene operates in the cell.”

Earlier studies have linked mutations in Rbfox1 to an increased risk for autism, which makes Rbfox1 an especially important gene to study. To better understand how Rbfox1 functions, Dr. Martin teamed up with Douglas Black, PhD, professor of microbiology, immunology and molecular genetics. The two blended a cell-biology approach with powerful DNA-sequencing technology to reveal the identities of the genes controlled by Rbfox1. “Our results turned up an exciting new set of genetic connections,” Dr. Black says. “We found that where Rbfox1 was located in the cell determined what genes it influenced.”

Ji-Ann Lee, PhD, a postdoctoral research fellow in Dr. Martin’s lab, compared Rbfox1’s function in the cell’s nucleus, or command center, to its function in the cytoplasm, the gel-like fluid that surrounds the cell’s nucleus. “Scientists used to think that Rbfox1 worked primarily in the nucleus to allow genes to make multiple proteins. We were surprised to see that Rbfox1 also controls more than 100 genes in the cytoplasm,” Dr. Lee says. “A majority of these genes encode proteins critical to the brain’s development and have been tied to autism risk.”

Furthermore, the genes controlled by Rbfox1 in the cell’s nucleus were completely different from those it controlled in the cell’s cytoplasm. The UCLA team’s separation of these two functions revealed that the genes targeted by Rbfox1 in the cell’s cytoplasm were highly enriched in proteins vital to the developing brain. Autism risk increases when these genes go awry. “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,” Dr. Martin says. “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.”

"Cytoplasmic Rbfox1 Regulates the Expression of Synaptic and Autism-related Genes,” Neuron, January 6, 2016


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