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Subject: AUTISM BLURS DISTINCTIONS BETWEEN BRAIN REGIONS
U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News
National Institute of Mental Health (NIMH) <http://www.nimh.nih.gov/>
For Immediate Release: Thursday, June 2, 2011
CONTACT: Jules Asher, NIMH press office, 301-443-4536,
<e-mail:[log in to unmask]>
AUTISM BLURS DISTINCTIONS BETWEEN BRAIN REGIONS
Erodes molecular identities in cortex - NIH-funded study
Autism
<http://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-pervasive-d
evelopmental-disorders/index.shtml> blurs the molecular differences that
normally distinguish different brain regions, a new study suggests. Among
more than 500 genes that are normally expressed at significantly different
levels in the front versus the lower middle part of the brain's outer
mantle, or cortex, only 8 showed such differences in brains of people with
autism, say researchers funded in part by the National Institutes of Health.
"Such blurring of normally differentiated brain tissue suggests strikingly
less specialization across these brain areas in people with autism,"
explained Daniel Geschwind, M.D., Ph.D., of the University of California,
Los Angeles, a grantee of the NIH's National Institute of Mental Health. "It
likely reflects a defect in the pattern of early brain development."
He and his colleagues published their study online May 26, 2011 in the
journal Nature. The research was based on postmortem comparisons of brains
of people with the disorder and healthy controls.
In fetal development, different mixes of genes turn on in different parts of
the brain to create distinct tissues that perform specialized functions.
The new study suggests that the pattern regulating this gene expression goes
awry in the cortex in autism, impairing key brain functions.
"This study provides the first evidence of a common signature for the
seemingly disparate molecular abnormalities seen in autism," said NIMH
director Thomas R. Insel, M.D. "It also points to a pathway-based framework
for understanding causes of other brain disorders stemming from similar
molecular roots, such as schizophrenia
<http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml> and ADHD
<http://www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disor
der-adhd/index.shtml>."
In an earlier study
<http://www.nimh.nih.gov/science-news/2008/genes-that-turn-on-together-hold-
secrets-of-brains-molecular-instructions.shtml>, the researchers showed that
genes that turn on and off together at the same time hold clues to the
brain's molecular instructions. These modules of co-expressed genes can
reveal genetic co-conspirators in human illness, through what Geschwind and
colleagues call "guilt by association." A gene is suspect if its expression
waxes and wanes in sync with others in an illness-linked module.
Using this strategy, the researchers first looked for gene expression
abnormalities in brain areas implicated in autism -- genes expressed at
levels different than in brains of healthy people. They found 444 such
differently expressed genes in the cortexes of postmortem brains of people
with autism.
Most of the same genes turned out to be abnormally expressed in the frontal
cortex as in the temporal cortex (lower middle) of autistic brains. Of
these, genes involved in synapses, the connections between neurons, tended
to be under-expressed when compared with healthy brains. Genes involved in
immune and inflammatory responses tended to be over-expressed.
Significantly, the same pattern held in a separate sample of autistic and
control brains examined as part of the study.
Autistic and healthy control brains were similarly organized -- modules of
co-expressed genes correlated with specific cell types and biological
functions.
Yet normal differences in gene expression levels between the frontal and
temporal cortex were missing in the modules of autistic brains. This
suggests that the normal molecular distinctions -- the tissue differences --
between these regions are nearly erased in autism, likely affecting how the
brain works. Strikingly, among 174 genes expressed at different levels
between the two regions in two healthy control brains, none were expressed
at different levels in brains of people with autism.
An analysis of gene networks revealed two key modules of co-expressed genes
highly correlated with autism.
One module was made up of genes in a brain pathway involved in neuron and
synapse development, which were under-expressed in autism. Many of these
genes were also implicated in autism in previous, genome-wide studies
<http://www.nimh.nih.gov/science-news/2008/autism-gene-scans-converge-on-two
-suspect-sites-two-types-of-genetic-risk.shtml>. So, several different
lines of evidence now converge, pointing to genes in this M12 module (see
picture below) as genetic causes of autism.
A second module of co-expressed genes, involved in development of other
types of brain cells, was over-expressed in autism. These were determined
not to be genetic causes of the illness, but likely gene expression changes
related to secondary inflammatory, immune, or possible environmental factors
involved in autism.
This newfound ability to see genes in the context of their positions in
these modules, or pathways, provides hints about how they might work to
produce illness, according to Geschwind and colleagues. For example, from
its prominent position in the M12 module, the researchers traced a potential
role in creating defective synapses to a gene previously implicated in
autism.
Follow-up studies should explore whether the observed abnormalities in the
patterning of gene expression might also extend to other parts of the brain
in autism, say the researchers.
The mission of the NIMH is to transform the understanding
About the National Institutes of Health (NIH): NIH, the nation's medical
research agency, includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. NIH is the primary federal
agency conducting and supporting basic, clinical, and translational medical
research, and is investigating the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.
-------------------------
REFERENCE: Transcriptomic analysis of autistic brain reveals convergent
molecular pathology <http://www.ncbi.nlm.nih.gov/pubmed/21614001>. Voineagu
I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, Mill J, Cantor RM,
Blencowe BJ, Geschwind DH. Nature. 2011 May 25. [Epub ahead of print]
PMID:21614001
-------------------------
IMAGE INFORMATION:
URL - <http://www.nimh.nih.gov/images/news-items/autism-genes.jpg>
Caption - A module of co-expressed genes that code for neurons and their
connections tend to be under-expressed in many individuals with autism
(red), compared to controls (gray).
Alt tag - Graph displaying genetic differences of autism
##
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