A ‘gold mine’ of drug targets for autism

LOS ANGELES—Seeking to ultimately find new and effective treatments for autism, a neurological disorder with no cure affecting one in 68 U.S. children alone, researchers at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), have discovered an untapped region in brain cells which contains mutated genes previously tied to autism.

This “uncharted territory” of the brain offers a gold mine of drug targets for new autism treatments, according to a study by UCLA researchers.

Recently published in Neuron, the discovery could provide fresh drug targets and lead to new therapies for the disorder, manifested by social, behavioral and speech issues.

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

Discovering an untapped region in brain cells may “not be the most groundbreaking,” Martin tells DDNews. “What is important about our study is that it describes a method for profiling gene expression in the cytoplasm, rather than just the entire cell. Recent studies have focused attention on examining gene expression in a cell type-specific manner, and we have extended this by analyzing gene expression within a subcellular compartment.”

“We define it as ‘cytoplasmic transcriptome profiling.’ Our findings indicate that the regulation of gene expression in the cytoplasm plays an especially important role in autism,” Martin explains. “The particular region of brain cells we investigated was not examined before because previous studies simply analyzed preparations which included all parts of nerve cells.”

Noting that gene sequencing technologies have revolutionized the ability to identify gene mutations underlying human diseases, she goes on to add, “We added a level of resolution by being able to focus on how genes are regulated in the nucleus and the cytoplasm. In the nucleus, gene expression involves synthesis of RNA from DNA. In the cytoplasm, gene expression involves the synthesis of RNA into protein. Our studies focus attention on the process of RNA to protein in cortical development and autism.”

The study provides insight into the cell biological processes that contribute to autism, and ultimately it is that, the UCLA researchers hope, that will lead to drugs that target these processes.

“Since we don’t understand the biology of autism, it’s not possible to determine which treatments will address language, social interactions, behavior,” Martin says. “It’s likely that these all result from similar molecular abnormalities and thus therapies that are based on a molecular understanding may affect many or all aspects of autism.”

The total cost of the UCLA study was approximately $500,000, covered by grants from the National Institute of Mental Health and a grant from the Brain and Behavior Research Foundation.

“Overall, this study focused on the cell biology of autism,” Martin said. “It is focused on fundamental brain biology and by the belief that this is the most effective way to develop new therapies for neuropsychiatric diseases.”

The next step is to determine how Rbfox1, the protein the team studied, regulates gene expression.

“Identifying a gene’s function is critical for molecular medicine,” said co-author Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics and a professor of neurology and psychiatry at UCLA. “My colleagues discovered that Rbfox1 has an entirely new function that other scientists had overlooked. 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.”

Earlier studies by Geschwind and others have linked mutations in Rbfox1 to an increased risk for autism. To better understand how Rbfox1 functions, Martin teamed up with UCLA molecular geneticist Douglas Black. 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,” said Black, a professor of microbiology, immunology and molecular genetics. “We found that where Rbfox1 was located in the cell determined what genes it influenced.”

The UCLA study’s first author is Ji-Ann Lee, a researcher in Martin’s lab. She 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,” Lee stated. “We were surprised to see that Rbfox1 also controls more than 100 genes in the cytoplasm.”

A majority of these genes encode proteins critical to the brain’s development, and have been tied to autism risk, she added. Furthermore, the genes controlled by Rbfox1 in the cell’s nucleus were completely different from those it controlled in the cell’s cytoplasm.

“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,” Martin said. “Autism risk increases when these genes go awry. While some experts have hinted at the role of cytoplasmic genes in autism risk, no one has explored it in actual cells before. Our study is the first to discover that dozens of autism risk genes reside in the cytoplasm and share common pathways in regulating the brain cells.”

Martin credits her interest in autism in large part to Geschwind’s leadership in the genetics of autism.

“In fact, the first funding we received for these studies came from a pilot study funded through Geschwind’s large NIH-funded Center for Autism Research and Treatment,” Martin says. “I would add that this has been very satisfying for me, as someone who has dedicated her career to basic cell and molecular neurobiology, because I was struck in medical school by how little we know about basic brain biology, and how much this limits our capacity to treat brain diseases.”