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Mon 29 Sep 2008 04:00 AM

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Research matters

News from the Harvard Medical School research community.

News from the Harvard Medical School research community.

Autism

Middle Eastern families yield intriguing clues to autism: Study implicates several genes involved in helping the brain learn from experience.

Research involving large Middle Eastern families, sophisticated genetic analysis and groundbreaking neuroscience has implicated a half-dozen new genes in autism.

In all, the technique identified five chromosome deletions affecting at least six identifiable genes.

More importantly, it strongly supports the emerging idea that autism stems from disruptions in the brain's ability to form new connections in response to experience - consistent with autism's onset during the first year of life, when many of these connections are normally made.

Interestingly, not all the affected genes were actually deleted, but only prevented from turning on - offering hope that therapies could be developed to reactivate the genes.

The study, led by researchers at Children's Hospital Boston and members of the Boston-based Autism Consortium, appears in the July 11 issue of Science.

Autism genes have been difficult to identify because the disorder is complex, with a variety of causes stemming from many possible genes or combinations of genes.

In addition, since people with autism tend not to have children, most of the genes identified thus far aren't inherited from a parent, but instead are mutated during embryonic development, making them hard to track through traditional linkage studies in families.

Christopher Walsh, MD, PhD, chief of genetics at Children's Hospital Boston, approached the problem by studying Middle Eastern families. In traditional Arab societies, it is common for cousins to marry, increasing the likelihood that offspring will inherit rare mutations.

Middle Eastern families also tend to have many children, making them ideal for mapping genes.

"To map a gene for autism in American families, averaging two to three kids per family, you would need to pool many families," says Walsh, who is also a Howard Hughes Medical Institute investigator at Beth Israel Deaconess Medical Center (BIDMC). "In larger families, one family alone may be enough to definitively localise a gene."

The Homozygosity Mapping Collaborative for Autism (HMCA) recruited 104 families with a high incidence of autism from the Arabic Middle East, Turkey and Pakistan; 88 of these families have cousin marriages.

Local clinicians were rigorously trained in administering standardised autism research assessments. Walsh's team later flew to sites in Turkey, Dubai, Kuwait and Saudi Arabia to confirm the diagnoses.

Using a technique called homozygosity mapping Walsh and colleagues compared the DNA of family members with and without autism, searching for recessive mutations - those that cause disease only when a child inherits two copies.

"We check each set of chromosomes from beginning to end, looking for one place where the child has two identical pieces of DNA on both chromosomes," Walsh explains. "Eventually we find a spot where all affected children have two identical chunks of DNA, and where unaffected children have something different."

Just over 6 percent of the 88 families showed rare, inherited deletions within DNA regions linked to autism. These affected DNA regions varied among families, further indication of autism's large variety of genetic causes.

In all, the technique identified five chromosome deletions affecting at least six identifiable genes (C3orf58, NHE9, PCDH10, contactin-3 [CNTN3], RNF8, and genes encoding a cluster of cellular sodium channels).

One of the genes, NHE9, was also found to be mutated in European and American children with autism (particularly those with both autism and seizures).

Experience-dependent learning: A common thread.

The genes discovered are diverse in function, but all seem to be part of a fundamental molecular network that orchestrates the refinement and maturation of brain connections, or synapses, in response to input from the outside world.

It is the refinement of these synaptic connections that is the basis of learning and memory, suggesting that autism at its heart may represent molecular defects of learning.

"This network can be disrupted in a myriad of ways, and may be one mechanism that people with a variety of autism-linked mutations share," says Michael Greenberg, PhD, a coauthor on the paper and director of the Neurobiology Program at Children's Hospital Boston. Normally, as a neuron (brain cell) receives an incoming message at the synapse, a network of reactions is sparked that extends all the way to its nucleus. Greenberg and his colleagues had long been mapping this network, and had previously found that it activates at least 300 genes.

These genes then communicate back to the neuron's surface, telling the cell to make a new synapse, strengthen the synapse that's already there, eliminate a synapse, or make a different kind of synapse.

This give-and-take system is how the brain builds its circuitry; neuroscientists call it "experience-dependent learning."

Patients with PD have clumps of alpha-synuclein in their brains and high levels of this protein kill off dopamine neurons and cause tremors and other symptoms of PD.

Working independently of Walsh, Greenberg and his colleagues had already identified three of the same genes found in the Middle Eastern patients (c3orf58, NHE9, and PCDH10) while looking for genes that turn on or off in neurons as part of this network - either in response to synaptic activity or through so-called transcription factors that are activated by synaptic activity.

The work bolsters a growing body of evidence that autism may represent a disruption of the brain's ability to modify its synaptic connections in response to experience.

"Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from the deregulation of any one of a number of genes that are part of the same signaling pathway," Greenberg says.

Can normal function be revived?

Interestingly, only one chromosome deletion found in the Middle Eastern families actually removed a gene - in most cases, what was lost was a region adjacent to the gene that contains its "on/off" switches.

This has important implications for therapy, because it suggests that autism mutations don't always remove a gene altogether, but only inhibit its activity in certain contexts, says Eric Morrow, MD, PhD, of Massachusetts General Hospital, who is co-first author of the paper with Seung-Yun Yoo, PhD.

"This means that we would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications," says Morrow, who also holds appointments at BIDMC and Children's.

The findings also support the use of behavioural therapies in autism, which expose children to a rich environment and highly repetitive activities that may help turn on the genes and strengthen synaptic connections, Morrow adds.

Parkinson's disease

Genetic mechanisms linked to Parkinson's Disease uncovered: Researchers show direct pathway which could be targeted for drug therapy.

A new genetic finding from a group of researchers at Brigham and Women's Hospital (BWH), the University of Wisconsin School of Medicine and Public Health (SMPH), and the University of Ottawa, may help pave the way for the discovery of therapies that could effectively treat Parkinson's disease (PD).

Clemens Scherzer, MD, a neurologist and researcher at BWH, along with collaborators, showed that the build up of a certain protein is responsible for controlling the production of the gene, alpha-synuclein, which is a cause of PD. These findings appear online and in print in the Proceedings of the National Academy of Science.

"This discovery is exciting because it allows for a paradigm shift in how researchers can search for a cure for Parkinson's disease. So far research has focused on ways to get rid of excess alpha-synuclein that is built up in the brain of patients with Parkinson's.

Now, we can look for ways to lower the production of alpha-synuclein upfront," Scherzer said.

Patients with PD have clumps of alpha-synuclein in their brains and high levels of this protein kill off dopamine neurons and cause tremors and other symptoms of PD.

While looking at blood tests for Parkinson's disease, the researchers noticed high levels of alpha-synuclein in the blood. Because alpha-synuclein was thought previously to be a gene found in the brain, its presence in the blood was surprising.

Seeking to uncover the reason for the presence of this gene in blood, they used gene chips to look at whether or not any of the thousands of other genes active in blood was linked to alpha-synuclein.They discovered that there are actually three genes, called heme genes, which are responsible for carrying oxygen and transporting electrons through the blood, whose activity was in lock step with the activity of the alpha-synuclein gene.

"In the middle of this noisy picture of gene expression in blood, we were able to uncover a very clear pattern of activity with these four genes," said Scherzer. "By recognising that pattern, we then deduced that there must be a switch, or mechanism that was responsible for controlling the activity of these genes."

The next step for researchers was to discover what was controlling the activity of these genes in the blood. For this, Dr. Scherzer and Dr. Schlossmacher, who leads the University of Ottawa research team, turned to Emery Bresnick, an SMPH professor of pharmacology, and an expert in GATA transcription factors.

This is another piece of data to show that diabetes, gallstones and cardiovascular disease are all causally linked to insulin resistance,” said Biddinger.

A transcription factor is a dial that turns the activity of genes up or down. Through this collaboration, researchers discovered that the transcription factor, GATA-1, was responsible for controlling the functions of these four genes in the blood and that a relative of GATA-1, the transcription factor GATA-2 - which is highly present in the brain regions affected by PD - may be responsible for the activity of alpha-synuclein in the brain.

"We were able to show that the GATA-2 transcription factor directly sticks to the alpha-synuclein gene and when GATA-2 was knocked down in dopamine cells, the levels of alpha-synuclein went down as well," said Dr. Schlossmacher.

This discovery illustrates the direct regulation of the gene by GATA factors, but researchers emphasise that further research is needed to understand if this pathway can be used for the development of drug therapies to tailor treatment strategies.

Gallstones and diabetes

Study by Joslin Diabetes Center finds insulin resistance causes gallstones.

It has been known for more than 100 years that gallstones are more common in obese individuals. Now, researchers at the Joslin Diabetes Center have determined that insulin resistance is likely the reason why.

"This is a very exciting discovery not only because we now have an answer to something that has been a puzzle for more than a century, but also because of its potential therapeutic implications," said lead author Sudha Biddinger, MD, PhD, a researcher in the Joslin Section on Obesity and Hormone Action.

The research, which is published in the current issue of Nature Medicine, demonstrates a link between insulin resistance and the development of gallstones in mice that lacked insulin receptors in their livers.

"Obesity is associated with increased secretion of cholesterol into the bile. The excess cholesterol accumulates in the gallbladder, which can lead to the formation of painful gallstones," said Biddinger.

"This study shows that insulin resistance is key to this process, as the lack of insulin receptors in the liver was sufficient to promote gallstones in that group of mice."

In the study, mice were fed a high-cholesterol diet for one week. Thirty-six percent of the insulin resistant mice developed gallstones, compared to none in the control group.

According to the paper, a regulatory protein involved in diabetes called FOXO1 is the cause. "FOXO1 is regulated by insulin, so when there is insufficient insulin, FOXO1 is turned on," Biddinger explained.

"This causes the liver to produce glucose, which leads to diabetes. This study demonstrates that FOXO1 also increases cholesterol secretion into the bile, leading to gallstones."

Gallstones are part of the metabolic syndrome, a collection of symptoms related to obesity - including glucose intolerance, hypertension, lowered HDL ("good") cholesterol and elevated triglycerides - that affects up to one-quarter of all Americans.

According to Biddinger, targeting FOXO1 with new drugs could prove effective in both the prevention and treatment of diabetes as well as gallstones. "We may be able to reverse or prevent elements of the metabolic syndrome," she said.

The finding also provides more evidence to show that the most important features of the metabolic syndrome do have a common cause."This is another piece of data to show that diabetes, gallstones and cardiovascular disease are all causally linked to insulin resistance," said Biddinger.

Research Matters brings together selected research being conducted at Harvard Medical School and its affiliated teaching hospitals and research institutes. For more information, visit the Harvard Medical School website at www.hms.harvard.edu.

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