RESEARCHAutism Changes Molecular Structure of the Brain

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Autism Changes Molecular Structure of the Brain: Discovery Points to a Common

Cause for Multifaceted Disease

For decades, autism researchers have faced a baffling riddle: how to

unravel a disorder that leaves no known physical trace as it develops in the

brain. Now a UCLA study is the first to reveal how the disorder makes its mark

at the molecular level, resulting in an autistic brain that differs dramatically

in structure from a healthy one. (Credit: © Tramper2 / Fotolia)

ScienceDaily — For decades, autism researchers have faced a baffling

riddle: how to unravel a disorder that leaves no known physical trace as it

develops in the brain.

Now a UCLA study is the first to reveal how the disorder makes its mark at

the molecular level, resulting in an autistic brain that differs dramatically in

structure from a healthy one. Published May 25 in the advance online edition of

Nature, the findings provide new insight into how genes and proteins go awry in

autism to alter the mind.

The discovery also identifies a new line of attack for researchers, who

currently face a vast array of potential fronts for tackling the neurological

disease and identifying its diverse causes.

" If you randomly pick 20 people with autism, the cause of each person's

disease will be unique, " said principal investigator Dr. Geschwind, the

Gordon and Virginia Mac Distinguished Chair in Human Genetics and a

professor of neurology and psychiatry at the Geffen School of Medicine at

UCLA. " Yet when we examined how genes and proteins interact in autistic people's

brains, we saw well-defined shared patterns. This common thread could hold the

key to pinpointing the disorder's origins. "

The research team, led by Geschwind, included scientists from the

University of Toronto and King's College London. They compared brain tissue

samples obtained after death from 19 autism patients and 17 healthy volunteers.

After profiling three brain areas previously linked to autism, the group zeroed

in on the cerebral cortex, the most evolved part of the human brain.

The researchers focused on gene expression -- how a gene's DNA sequence is

copied into RNA, which directs the synthesis of cellular molecules called

proteins. Each protein is assigned a specific task by the gene to perform in the

cell.

By measuring gene-expression levels in the cerebral cortex, the team

uncovered consistent differences in how genes in autistic and healthy brains

encode information.

" We were surprised to see similar gene expression patterns in most of the

autistic brains we studied, " said first author Irina Voineagu, a UCLA

postdoctoral fellow in neurology. " From a molecular perspective, half of these

brains shared a common genetic signature. Given autism's numerous causes, this

was an unexpected and exciting finding. "

The researchers' next step was to identify the common patterns. To do

this, they looked at the cerebral cortex's frontal lobe, which plays a role in

judgment, creativity, emotions and speech, and at its temporal lobes, which

regulate hearing, language and the processing and interpreting of sounds.

When the scientists compared the frontal and temporal lobes in the healthy

brains, they saw that more than 500 genes were expressed at different levels in

the two regions.

In the autistic brains, these differences were virtually non-existent.

" In a healthy brain, hundreds of genes behave differently from region to

region, and the frontal and temporal lobes are easy to tell apart, " Geschwind

said. " We didn't see this in the autistic brain. Instead, the frontal lobe

closely resembles the temporal lobe. Most of the features that normally

distinguish the two regions had disappeared. "

Two other clear-cut patterns emerged when the scientists compared the

autistic and healthy brains. First, the autistic brain showed a drop in the

levels of genes responsible for neuron function and communication. Second, the

autistic brain displayed a jump in the levels of genes involved in immune

function and inflammatory response.

" Several of the genes that cropped up in these shared patterns were

previously linked to autism, " said Geschwind. " By demonstrating that this

pathology is passed from the genes to the RNA to the cellular proteins, we

provide evidence that the common molecular changes in neuron function and

communication are a cause, not an effect, of the disease. "

The next step will be for the research team to expand its search for the

genetic and related causes of autism to other regions of the brain.

Autism is a complex brain disorder that strikes in early childhood. The

disease disrupts a child's ability to communicate and develop social

relationships and is often accompanied by acute behavioral challenges. In the

United States, autism spectrum disorders are diagnosed in one in 110 children --

and one in 70 boys. Diagnoses have expanded tenfold in the last decade.

The study was funded by the National Institute of Mental Health, the

Canadian Institutes of Health Research, and Genome Canada. Tissue samples were

provided by the Autism Tissue Project, the Harvard Brain Bank and the Medical

Research Council's London Brain Bank for Neurodegenerative Disease.

Geschwind's and Voineagu's co-authors included Lowe, Yuan Tian,

Steve Horvath, Mill and Rita Cantor of UCLA; Blencowe and

Xinchen Wang of the University of Toronto; and ston of King's

College London.