A team of UCLA scientists has discovered important clues as to what goes wrong in the brains of people with autism. The new insights involve RNA editing — in which genetic material is normal but modifications in RNA alter nucleotides, whose patterns carry the data required for constructing proteins.
“RNA editing is probably having a substantial physiologic effect in the brain but is poorly understood,” says Daniel Geschwind, MD (RES ’95, FEL ’97), Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology and Psychiatry and director of UCLA’s Institute for Precision Health. “RNA editing is a mysterious area, whose biological implications have not been much explored. We know what only a handful of these RNA-editing sites do to proteins. This study, which is the first comprehensive study of RNA editing in autism spectrum disorders, gives a new critical clue in understanding what has gone awry in the brains of autism patients.
The researchers analyzed brain samples from 69 people who died, about half of whom had autism spectrum disorder (which includes autism and related conditions) and about half of whom did not and served as a control group. Xinshu (Grace) Xiao, PhD, Maria R. Ross Professor of Integrative Biology and Physiology and director of UCLA’s bioinformatics interdepartmental graduate program, and her research team analyzed 7 billion nucleotides for each brain sample. Dr. Xiao’s team discovered reduced editing in the group members with autism. Specifically, they identified 3,314 editing sites in the brain’s frontal cortex, in which the autism patients had different levels of RNA editing from the control group. In 2,308 of those sites, the individuals with autism had reduced RNA editing. In the 1,006 others, they had increased levels of RNA editing.
In the brain’s temporal cortex, the people with autism had different levels of RNA editing from the control group in 2,412 editing sites, with 1,471 of those sites showing reduced editing levels. In the brain’s cerebellum, the autism group members had different levels of RNA editing from control group members in 4,340 sites, of which 3,330 sites in the autistic brain had decreased levels. All three of these brain regions are very important in autism.
Dr. Xiao says that one can think of RNA editing as RNA mutations, analogous to the DNA mutations that are linked to many diseases. “The same piece of DNA can generate multiple versions of RNA and possibly lead to different protein sequences,” she says. “RNA editing allows cells to create novel protein sequences that are not written in the DNA.”
In another major finding, the researchers identified two proteins, called FMRP and FXR1P, that regulate abnormal RNA editing in autism spectrum disorder. FMRP increases RNA editing and FXR1P decreases RNA editing, the researchers discovered. The autism group had reduced editing levels regulated by FMRP, as well as reduced RNA editing overall. “This is the first strong data showing a broad and direct functional role for FMRP and FXR1P in the human brain and autism,” Dr. Xiao says.
It currently is unknown if the changes the people with autism had in RNA editing caused their autism, contributed to the disorder or were a result of it. “We can’t assign causality,” Dr. Geschwind says.
RNA editing also may be disrupted in schizophrenia, bipolar disorder and major depression. The research team plans to continue to study this as well as other brain diseases.
— Stuart Wolpert
“Widespread RNA Editing Dysregulation in Brains from Autistic Individuals,” Nature Neuroscience, December 17, 2018