Brains of People With Autism Spectrum Disorder Share Similar Molecular Abnormalities

Summary: Researchers discover similar signature molecular abnormalities in the brains of people with ASD.

Source: UCLA.

UCLA study shows a distinctive pattern of unusual gene activity.

Autism spectrum disorder is caused by a variety of factors, both genetic and environmental. But a new study led by UCLA scientists provides further evidence that the brains of people with the disorder tend to have the same “signature” of abnormalities at the molecular level.

The scientists analyzed 251 brain tissue samples from nearly 100 deceased people — 48 who had autism and 49 who didn’t. Most of the samples from people with autism showed a distinctive pattern of unusual gene activity.

The findings, published Dec. 5 in Nature, confirm and extend the results of earlier, smaller studies, and provide a clearer picture of what goes awry, at the molecular level, in the brains of people with autism.

“This pattern of unusual gene activity suggests some possible targets for future autism drugs,” said Dr. Daniel Geschwind, the paper’s senior author and UCLA’s Gordon and Virginia MacDonald Distinguished Professor of Human Genetics. “In principle, we can use the abnormal patterns we’ve found to screen for drugs that reverse them — and thereby hopefully treat this disorder.”

According to the Centers for Disease Control and Prevention, about 1.5 percent of children in the U.S. have autism; the disorder is characterized by impaired social interactions and other cognitive and behavioral problems. In rare cases, the disorder has been tied to specific DNA mutations, maternal infections during pregnancy or exposures to certain chemicals in the womb. But in most cases, the causes are unknown.

In a much-cited study in Nature in 2011, Geschwind and colleagues found that key regions of the brain in people with different kinds of autism had the same broad pattern of abnormal gene activity. More specifically, researchers noticed that the brains of people with autism didn’t have the “normal” pattern for which genes are active or inactive that they found in the brains of people without the disorder. What’s more, the genes in brains with autism weren’t randomly active or inactive in these key regions, but rather had their own consistent patterns from one brain to the next — even when the causes of the autism appear to be very different.

The discovery suggested that different genetic and environmental triggers of autism disorders mostly lead to disease via the same biological pathways in brain cells.

In the new study, Geschwind and his team analyzed a larger number of brain tissue samples and found the same broad pattern of abnormal gene activity in areas of the brain that are affected by autism.

“Traditionally, few genetic studies of psychiatric diseases have been replicated, so being able to confirm those initial findings in a new set of patients is very important,” said Geschwind, who also is a professor of neurology and psychiatry at the David Geffen School of Medicine at UCLA. “It strongly suggests that the pattern we found applies to most people with autism disorders.”

Image shows a brain and DNA.
According to the Centers for Disease Control and Prevention, about 1.5 percent of children in the U.S. have autism; the disorder is characterized by impaired social interactions and other cognitive and behavioral problems. In rare cases, the disorder has been tied to specific DNA mutations, maternal infections during pregnancy or exposures to certain chemicals in the womb. But in most cases, the causes are unknown. NeuroscienceNews image is for illustrative purposes only.

The team also looked at other aspects of cell biology, including brain cells’ production of molecules called long non-coding RNAs, which can suppress or enhance the activity of many genes at once. Again, the researchers found a distinctive abnormal pattern in the autism disorder samples.

Further studies may determine which abnormalities are drivers of autism, and which are merely the brain’s responses to the disease process. But the findings offer some intriguing leads about how the brains of people with autism develop during the first 10 years of their lives. One is that, in people with the disorder, genes that control the formation of synapses — the ports through which neurons send signals to each other — are abnormally quiet in key regions of the brain. During the same time frame, genes that promote the activity of microglial cells, the brain’s principal immune cells, are abnormally busy.

This could mean that the first decade of life could be a critical time for interventions to prevent autism.

The study also confirmed a previous finding that in the brains of people with autism, the patterns of gene activity in the frontal and temporal lobes are almost the same. In people who don’t have autism, the two regions develop distinctly different patterns during childhood. The new study suggests that SOX5, a gene with a known role in early brain development, contributes to the failure of the two regions to diverge in people with autism.

About this autism research article

The study’s lead authors are Neelroop Parikshak, Vivek Swarup and Grant Belgard of UCLA; other co-authors are Gokul Ramaswami, Michael Gandal, Christopher Hartl, Virpi Leppa, Luis de la Torre Ubieta, Jerry Huang, Jennifer Lowe and Steve Horvath of UCLA; Manuel Irimia of the Barcelona Institute of Science and Technology; and Benjamin Blencowe of the University of Toronto.

Funding: The research was funded in part by the National Institutes of Health.

Source: Mark Wheeler – UCLA
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism” by Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Manuel Irimia, Gokul Ramaswami, Michael J. Gandal, Christopher Hartl, Virpi Leppa, Luis de la Torre Ubieta, Jerry Huang, Jennifer K. Lowe, Benjamin J. Blencowe, Steve Horvath and Daniel H. Geschwind in Nature. Published online December 5 2016 doi:10.1038/nature20612

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]UCLA. “Brains of People With Autism Spectrum Disorder Share Similar Molecular Abnormalities.” NeuroscienceNews. NeuroscienceNews, 4 December 2016.
<https://neurosciencenews.com/asd-brain-molecular-abnormalities-6687/>.[/cbtab][cbtab title=”APA”]UCLA. (2016, December 4). Brains of People With Autism Spectrum Disorder Share Similar Molecular Abnormalities. NeuroscienceNews. Retrieved December 4, 2016 from https://neurosciencenews.com/asd-brain-molecular-abnormalities-6687/[/cbtab][cbtab title=”Chicago”]UCLA. “Brains of People With Autism Spectrum Disorder Share Similar Molecular Abnormalities.” https://neurosciencenews.com/asd-brain-molecular-abnormalities-6687/ (accessed December 4, 2016).[/cbtab][/cbtabs]


Abstract

Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism

Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.

“Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism” by Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Manuel Irimia, Gokul Ramaswami, Michael J. Gandal, Christopher Hartl, Virpi Leppa, Luis de la Torre Ubieta, Jerry Huang, Jennifer K. Lowe, Benjamin J. Blencowe, Steve Horvath and Daniel H. Geschwind in Nature. Published online December 5 2016 doi:10.1038/nature20612

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