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Fragile X syndrome traits may stem from leaky mitochondria

Hole picture: Leaks in the mitochondrial membrane may cause fragile X neurons to get stuck in an immature state.

Many problems associated with fragile X syndrome stem from a leak in mitochondria, organelles that act as the power stations of the cell, a new study suggests1. Stopping this leak eases some of the autism-like traits of mice that model the syndrome.

“The paper is very solid,” says John Jay Gargus, director of the Center for Autism Research and Translation at the University of California, Irvine, who was not involved in the study. And because mitochondrial energy deficiency is seen in other forms of autism, the findings may be relevant beyond fragile X syndrome, Gargus says.

Fragile X syndrome results from mutations in the FMR1 gene, which lead to a loss of the protein FMRP. Without FMRP, cells have immature dendritic spines — the bumps along a neuron’s arms that receive input from other neurons — and produce other proteins in excess. These differences are thought to contribute to the syndrome’s characteristic traits, such as developmental delay, intellectual disability and, often, autism.

The new study shows that a leak in the mitochondrial membrane, possibly caused by the lack of FMRP, may drive the affected cells’ immaturity and excess protein production. The leak affects a cell’s metabolism, causing it to produce energy quickly but not efficiently, says lead researcher Elizabeth Jonas, professor of internal medicine and neuroscience at Yale University.

All cells start out with mitochondrial leaks; the rapid energy production these leaks allow may be useful in early development. As typical cells mature and efficiency becomes more important than speed, however, they seem to close the leaks, Jonas says. Because cells with a fragile X mutation cannot close their leaks, they remain in an immature state.

Applying a compound that blocks the leaks leads to more mature metabolism and decreases protein production in neurons from fragile X syndrome model mice and in fibroblasts from people with the syndrome, the researchers found. And injecting fragile X model mice with the compound decreases their autism-like behaviors.

“It shows a very nice target: a single channel that can be manipulated,” says study investigator Pawel Licznerski, associate research scientist in medicine at Yale University.

Leaky membranes:

Jonas, Licznerski and their colleagues observed that mitochondria from fragile X mice are smaller and produce less adenosine triphosphate (ATP), the molecule that transfers energy throughout cells, compared with controls.

A lollipop-shaped enzyme embedded within the mitochondrial membrane called ATP synthase produces ATP by pumping hydrogen ions into the organelle’s inner chamber and preventing them from leaking back out.

To see if the dearth of ATP was due to a problem with ATP synthase, the researchers isolated vesicles — bubbles of mitochondrial membrane containing ATP synthase — from fragile X mice and control mice. They put the vesicles into a bath containing dye that fluoresces when hydrogen ions are present.

ATP synthase from typical mice pumped all of the hydrogen ions into the vesicles and trapped them there, decreasing the intensity of fluorescence in the bath. But the bath with vesicles from fragile X mice remained highly fluorescent; the fragile X vesicles “couldn’t sequester any hydrogen ions,” Jonas says.

Vesicles from fragile X model mice also had significantly greater ‘membrane conductance,’ a sign that hydrogen ions move continuously in and out of the vesicles. This result suggests that the synthase can pump ions in, but they somehow leak back out through the membrane.

Treating the vesicles with the compound dexpramipexole blocked the leak and decreased the conductance, the researchers found. The work was published in August in Cell.

Metabolic boosts:

ATP synthase comprises multiple subunits. Compared with mitochondria in typical neurons, those in fragile X neurons have a significantly greater proportion of one subunit, called the c-subunit, the researchers found. This imbalance could explain why these mitochondria cannot trap hydrogen ions: The c-subunits can exist by themselves as channels in the mitochondrial membrane and allow hydrogen ions to leak out.

To close those channels, a cell must incorporate the c-subunits into new ATP synthases, a process that requires another subunit, called beta. The protein missing in people with fragile X syndrome, FMRP, regulates the manufacture of beta subunits, the researchers found. Unable to regulate how beta subunits are produced, Jonas and her colleagues say, mitochondria in the cells of fragile X mice remain leaky.

The persistent leak influences which metabolic pathway the cell uses to generate energy, the team discovered by using a technique called mass spectrometry. For example, fragile X neurons produce more enzymes associated with glycolysis — a pathway commonly used by immature cells — than do typical neurons. Previous studies have shown altered mitochondrial metabolism in people with other forms of autism2.

Adding dexpramipexole to the cells of fragile X mice decreased production of lactate dehydrogenase and other enzymes linked to glycolysis, suggesting that closing the leak causes the neurons to start to use different, more mature metabolic pathways.

Giving injections of dexpramipexole to fragile X model mice lessened their hyperactivity, repetitive behaviors and excessive grooming — traits that are reminiscent of those seen in people with autism and in those with fragile X syndrome. Mice that received the dexpramipexole injections also had neurons with more mature dendritic spines and decreased levels of protein synthesis.

Channel changes:

Though interesting, the findings “do not provide a clear mechanism for how FMRP regulates the leak,” says Xinyu Zhao, professor of neuroscience at the University of Wisconsin-Madison, who was not involved in the study. Research by Zhao and her colleagues suggests that an interaction between FMRP and another protein is necessary for mitochondria to function properly and for cells to mature3.

Even without a mechanism, being able to ease autism-like traits in mice by closing one membrane channel “is remarkable,” Licznerski says. “This opens the door to a new approach to therapy” for people with fragile X syndrome, he says.

Others urge caution: There is no guarantee that a treatment that works in mice will work in the human brain, says Cecilia Giulivi, professor of molecular biosciences at the University of California, Davis MIND Institute, who was not involved in the study. She is concerned that these preliminary results will offer false hope to the families of people with fragile X syndrome and encourage people to seek out treatments that have not been proven safe. Dexpramipexole has been tested in people with the neurological disease amyotrophic lateral sclerosis and found safe, but it is unclear how it would affect young people if taken over sustained periods of time.

Before a treatment is possible, Jonas and Licznerski say they need to better understand how the ATP synthase subunits contribute to the leak. As part of that goal, they are engineering mice without extra c-subunits to see if minimizing the leak in that way has the same effect as applying dexpramipexole.

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THIS NOTICE DESCRIBES HOW MEDICAL INFORMATION ABOUT YOU MAY BE USED AND DISCLOSED AND HOW YOU CAN GET ACCESS TO THIS INFORMATION. PLEASE REVIEW IT CAREFULLY.

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We may use and disclose your protected health information in the following instances. You have the opportunity to agree or object to the use or disclosure of all or part of your protected health information. If you are not present or able to agree or object to the use or disclosure of the protected health information, then we may, using professional judgment, determine whether the disclosure is in your best interest.

Others Involved in Your Health Care or Payment for our Care:

Unless you object, we may disclose to a member of your family, a relative, a close friend or any other person you identify, your protected health information that directly relates to that person's involvement in your health care. If you are unable to agree or object to such a disclosure, we may disclose such information as necessary if we determine that it is in your best interest based on our professional judgment. We may use or disclose protected health information to notify or assist in notifying a family member, personal representative or any other person that is responsible for your care of your location, general condition or death. Finally, we may use or disclose your protected health information to an authorized public or private entity to assist in disaster relief efforts and to coordinate uses and disclosures to family or other individuals involved in your health care.
6. Uses and Disclosures of Protected Health Information Based upon Your Written Authorization Other uses and disclosures of your protected health information will be made only with your written authorization, unless otherwise permitted or required by law as described below. You may revoke this authorization in writing at any time. If you revoke your authorization, we will no longer use or disclose your protected health information for the reasons covered by your written authorization. Please understand that we are unable to take back any disclosures already made with your authorization.
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Following is a statement of your rights with respect to your protected health information and a brief description of how you may exercise these rights
1. You have the right to inspect and copy your protected health information
This means you may inspect and obtain a copy of protected health information about you for so long as we maintain the protected health information. You may obtain your medical record that contains medical and billing records and any other records that we use for making decisions about you. As permitted by federal or state law, we may charge you a reasonable copy fee for a copy of your records.
2. You have the right to request a restriction of your protected health information
This means you may ask us not to use or disclose any part of your protected health information for the purposes of treatment, payment or health care operations. You may also request that any part of your protected health information not be disclosed to family members or friends who may be involved in your care or for notification purposes as described in this Notice of Privacy Practices. Your request must state the specific restriction requested and to whom you want the restriction to apply.

We are not required to agree to a restriction that you may request. If we agree to the requested restriction, we may not use or disclose your protected health information in violation of that restriction unless it is needed to provide emergency treatment. With this in mind, please discuss any restriction you wish to request with your health provider.

You may request a restriction by making your request in writing to our Privacy Officer. In your request, you must tell us (1) what information you want to limit; (2) whether you want to limit our use, disclosure, or both; and (3) to whom you want the limits to apply, for example, disclosures to your spouse.
3. You have the right to request to receive confidential communications from us by alternative means or at an alternative location
We will accommodate reasonable requests. We may also condition this accommodation by asking you for information as to how payment will be handled or specification of an alternative address or other method of contact. We will not request an explanation from you as to the basis for the request. Please make this request in writing to our Privacy Officer.
4. Your may have right to amend your protected health information
This means you may request an amendment of protected health information about you in a designated record set for so long as we maintain this information. In certain cases, we may deny your request for an amendment. If we deny your request for amendment, you have the right to file a statement of disagreement with us and we may prepare a rebuttal to your statement and will provide you with a copy of any such rebuttal. Please contact our Privacy Officer if you have questions about amending your medical record.
5. You have the right to receive an accounting of certain disclosures we have made, if any, of your protected health information This right applies to disclosures for purposes other than treatment, payment or health care operations as described in this Notice of Privacy Practices. It excludes disclosures we may have made to you if you authorized us to make the disclosure, to family members or friends involved in your care, or for notification purposes, for national security or intelligence, to law enforcement (as provided in the privacy rule) or correctional facilities, as part of a limited data set disclosure. The right to receive this information is subject to certain exceptions, restrictions and limitations.
6. You have the right to obtain a paper copy of this notice from us
upon request, even if you have agreed to accept this notice electronically.
D. COMPLAINTS
You may complain to us or to the Secretary of Health and Human Services if you believe your privacy rights have been violated by us. You may file a complaint with us by notifying our Privacy Officer of your complaint. We will not retaliate against you for filing a complaint

You may contact our Privacy Officer at (704) 824-7800 for further information about the complaint process.

This notice was published and becomes effective on August l, 2011.