神経シナプス接合蛋白の遺伝子変異が自閉症に関連

 神経細胞間のシナプス接合蛋白のうち neuroligin-1 と neuroligin-2 の2つの蛋白の遺伝子変異が自閉症に関連している。
 神経細胞活動の興奮と抑制に関連する蛋白で、自閉症ではこのバランスが失われる。

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Last Updated: Thursday, 21 June 2007, 00:05 GMT 01:05 UK
Protein mutations link to autism
http://news.bbc.co.uk/2/hi/health/6221064.stm

画像Boy with autism
Autism impairs social interaction

Scientists have discovered how mutations in two key proteins may lead to autism.
They have shown one protein increases the excitability of nerve cells, while the other inhibits cell activity.
The University of Texas team found that in normal circumstances the proteins balance each other out.
But the study, published in Neuron, suggests that in people with autism the balance between the proteins is knocked out of kilter.
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Understanding how the autistic brain is different to the neurotypical brain will have significant implications for education and intervention
Professor Simon Baron-Cohen
University of Cambridge
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The findings back the theory that autism involves an imbalance between excitatory and inhibitory connections between nerve cells.
The proteins, which serve to physically link nerve cells together, were discovered by the team at the university's Southwestern Medical Center more than a decade ago.
However, until the latest study their exact function had been unclear.
Lead researcher Dr Ege Kavalali said: "Mutations in these proteins have recently been linked to certain varieties of autism.
"This work provides clear insight into how the proteins function. We can never design a therapeutic strategy without knowing what these mutations do."
Bridge between cells
The proteins - neuroligin-1 and neuroligin-2 - create a physical bridge at the junction - or synapse - of nerve cells, enabling them to make connections with others.
In studies on rats the researchers showed that raising levels of both proteins in nerve cells led to the creation of extra synapses.
Neuroligin-1 was associated with excitatory connections and neuroligin-2 with inhibitory connections.
When they introduced a mutant form of neuroligin-1 thought to be carried by some people with autism the number of synapses fell dramatically - and the cells became significantly less excitable.
Infants are born with far more synapses than survive to adulthood. Active synapses proliferate during development, but inactive synapses are culled.
The latest research suggests that carrying a mutant form of neuroligin-1 may depress the number of synapses that make it into adulthood.
This could hamper the ability of nerve cells to make the usual connections, and lead to the deficits seen in people with autism.
It affects the way a person communicates and interacts with other people.
Communication problems
People with autism cannot relate to others in a meaningful way. They also have trouble making sense of the world at large.
As a result, their ability to develop friendships is impaired. They also have a limited capacity to understand other people's feelings.
Autism is often also associated with learning disabilities.
Professor Simon Baron-Cohen, director of the Autism Research Centre at the University of Cambridge, said research into the role of neuroligins in autism was important.
He said: "We need to know more about both the genes that code for neuroligins, and the neuroligins themselves, to establish if they play a specific role in the cause of autism spectrum conditions and in which subgroup.
"Understanding how the autistic brain is different to the neurotypical brain will have significant implications for education and intervention."

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Autism-related proteins control nerve excitability, researchers find

http://www.utsouthwestern.edu/utsw/cda/dept353744/files/389615.html
画像The University of Texas Southwestern Medical Center at Dallas

DALLAS ― June 20, 2007 ― Two proteins that are implicated in autism have been found to control the strength and balance of nerve-cell connections, researchers at
UT Southwestern Medical Center have found.

The proteins, which serve to physically link nerve cells together, were discovered more than a decade ago by UT Southwestern scientists, but their function has been unclear.
In the new study, which appears in the June 21 edition of the journal Neuron, the researchers found that one protein increases the excitability of nerve cells, while the other inhibits cell activity. Most importantly, these effects depended on how often the cells fired.
Kavalali_low res
A research team that included (from left) Drs. Jay Gibson, associate professor of neuroscience, Ege Kavalali, associate professor of neuroscience and physiology, and Thomas Su"dhof, chairman of neuroscience, has discovered that two proteins implicated in autism control the strength and balance of nerve-cell connections.
The activity levels of neurons play a vital role during normal brain development in children. Active connections become stronger and survive to adulthood, while inactive ones disappear.
Autism is believed to involve an imbalance of excitatory and inhibitory nerve connections, a theory supported by this study, said Dr. Ege Kavalali, associate professor of neuroscience and physiology at UT Southwestern and an author of the paper.
“Mutations in these proteins have recently been linked to certain varieties of autism,” Dr. Kavalali said. “This work provides clear insight into how the proteins function. We can never design a therapeutic strategy without knowing what these mutations do.”
The proteins are called neuroligin-1 and neuroligin-2. At the junction of two nerve cells, called a synapse, the proteins stick out from the surface of the cell that receives a signal from the first cell. The neuroligins bind to other molecules on the first cell, thus creating a physical bridge across the synapse.
In some cases, a signal from the first cell excites the second cell, while at other synapses, the signal inhibits the second cell.
Infants are born with far more synapses, both excitatory and inhibitory, than adults end up with. In a process called pruning, synapses that are inactive during development disappear while active ones proliferate.
In the current study, the researchers genetically manipulated rat neurons in culture so that the cells created too much neuroligin-1. The cells developed twice the usual number of synapses, raising the question of whether neuroligin-1 contributed to the formation of additional synapses or contributed to the failure of existing ones to be pruned. Similar tests showed that excess neuroligin-2 also led to more synapses, but in this case, the synapses were inhibitory.
When the cells that overexpressed either neuroligin-1 or neuroligin-2 were chemically prevented from firing, they did not develop excess synapses, despite the presence of the respective proteins.
Together, the tests indicate that nerve cells with excess neuroligins developed extra synapses only when those cells are allowed to fire.
“The two neuroligins have complementary roles under normal conditions, with neuroligin-1 increasing the excitatory links between nerve cells, and neuroligin-2 increasing the number of inhibitory links, creating a balance,” Dr. Kavalali said. “In both cases, the neuroligins are not necessary for creating the synapses, but they have a role in determining which synapses make it in the long run, and thus setting up how responsive the nerve cells are.”
Because mutations in neuroligins occur in some people with autism spectrum disorders, the researchers also engineered a mutation in neuroligin-1 comparable to one observed in humans and introduced the mutant neuroligins into rat neurons.
“The nerve cells carrying the mutant neuroligin showed a dramatic decrease in the number of synapses and a more than twofold decrease in excitability, showing that the mutation interferes with the stability of the synapses,” Dr. Kavalali said.
Other UT Southwestern researchers involved in the study were Dr. Alexander Chubykin, a former graduate student now at MIT; graduate student Deniz Atasoy; medical student Mark Etherton; Dr. Nils Brose, a former postdoctoral researcher in molecular genetics now at the Max Planck Institute for Experimental Medicine in Germany; Dr. Jay Gibson, associate professor of neuroscience; and Dr. Thomas Su"dhof, chairman of neuroscience.

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