More than 24 million people worldwide are estimated to have autism. In developed countries, about 1.5% of children have been diagnosed with autism spectrum disorder as of 2017. The disorder affects communication and behavior, and is marked by problems in social communication and social interaction, and repetitive behaviors. A team of UCLA-led scientists has discovered important clues to what goes wrong in the brains of people with autism — a developmental disorder with no cure and for which scientists have no deep understanding of what causes it. The new data involve RNA editing – a cellular process in which genetic material is normal, but modifications in RNA alter nucleotides, whose patterns carry the data required for constructing proteins. RNA editing is most likely having a physiologic effect in the brain, but is poorly understood. RNA editing is a mysterious area whose biological implications have not been much explored. Scientists know what only a handful of these RNA editing sites do to proteins. This study 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. The research team analyzed seven billion nucleotide bases for each brain sample and 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, Tran said. 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.
RNA editing can be thought of 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. This way, RNA editing allows cells to create novel protein sequences that are not written in the DNA. Scientists had long assumed that a sequence of RNA is a faithful copy of a gene’s DNA sequence — and that RNA is merely the cellular messenger that carries out DNA’s instructions to other parts of the cell. This assumption was proved to be wrong when RNA editing was first discovered in the 1980s. Scientists are finding many examples where the genetic codes we inherit from our parents are edited in our cells. 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, Tran 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.
Looks like that something about what FMRP does is clearly critical to autism pathogenesis. It is currently unknown whether the changes the people with autism had in RNA editing caused their autism, contributed to the disorder or were a result of it. RNA editing may also be disrupted in schizophrenia, bipolar disorder and major depression. The research team plans to continue to study this as well as other brain diseases. The team replicated their findings by analyzing the frontal cortex from a different group of 22 people who had autism spectrum disorder and a control group of 23 without the disorder. They found the same pattern of editing reduction as they found originally. The researchers found RNA editing alterations in genes of critical neurological relevance to autism, including ANK2, CNTNAP2, CNTNAP4, NRXN1, NRXN3, NOVA1 and RBFOX1. Scientists used powerful methods of bioinformatics and statistics to identify the RNA editing sites. Usually, in searching for causes of diseases, most research has focused on searching for mutations in the DNA. The research, published in the journal Nature Neuroscience, is the first comprehensive study of RNA editing in autism spectrum disorder.
In another study published this January 17 in Translational Psychiatry, researchers at University of California San Diego School of Medicine describe how, in a novel mouse model, epigenetic regulation negatively impacts a downstream gene specifically involved in brain development and associated behaviors. They only had clinical and genetic evidence that the gene was related to autism. Now, with this mouse model, they found have direct causal evidence linking this gene with neuronal molecular and cellular alterations leading to ASD-like behavior. The research was led by senior author Alysson R. Muotri, PhD, professor in the UC San Diego School of Medicine departments of Pediatrics and Cellular and Molecular Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine. The team focused on what is called epigenetic modification. Epigenetics refers to changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself.
Epigenetic control of chromatin structure — how DNA is efficiently packaged within a cell’s nucleus — mediates many critical cellular processes, from gene expression to cell division and neural development. The importance of epigenetic regulatory mechanisms is increasingly appreciated in human neurodevelopment and neurodevelopmental conditions, such as ASD. Indeed, mutations in chromatin-related epigenetic genes can cause several neurological disorders. That is why Dr. Muotri and colleagues looked specifically at a group of proteins called the SET domain which write instruction code for histone methylation, a process of adding or subtracting proteins to increase or decrease gene transcription. It is critical to the regulation of gene expression and the ability of different cells to express different genes. SET domain proteins mediate a gene called SETD5, which is essential to neurodevelopment and has been categorized, in clinical genetic studies, as a top ASD-risk gene.
But until now there was no causal relation between SETD5 loss of function and alterations in neurodevelopment. Working in a mouse model with only one functional copy of the SETD5 gene, the researchers found that cortical neurons displayed morphological alterations and reduced connectivity. As a consequence, the neuronal networks showed a delayed in development in these mice compared to controls. The researchers then traced which genes were affected, identifying neurodevelopmental pathways that are targeted by the SETD5 gene. They hypothesized that the affected gene expression would likely result in altered behavior and, in fact, observed abnormal patterns of social interaction and “autism-compatible” behavior in the mice. Magnetic resonance imaging analyses revealed subtle anatomical differences in the mutant adult brain of affected mice. A more detailed anatomical investigation revealed aberrant cortical lamination — a phenotype observed in other ASD mouse models as well.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Tran SS et al., Xiao X. Nature Neurosci. 2019 Jan; 22(1):25-36.
Moore SM et al., Muotri AR. Transl Psychiatry 2019 Jan 17; 9(1):24.
Fernandes IR et al. Muotri AR. Dev Neurobiol. 2018 May; 78(5):500.