Unraveling the molecular roots of Down syndrome

By Heather Buschman, Ph.D.
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Researchers discover that the extra chromosome inherited in Down syndrome impairs learning and memory because it leads to low levels of SNX27 protein in the brain.

What is it about the extra chromosome inherited in Down syndrome—chromosome 21—that alters brain and body development? Researchers have new evidence that points to a protein called sorting nexin 27, or SNX27. SNX27 production is inhibited by a molecule encoded on chromosome 21. The study, published March 24 in Nature Medicine, shows that SNX27 is reduced in human Down syndrome brains. The extra copy of chromosome 21 means a person with Down syndrome produces less SNX27 protein, which in turn disrupts brain function. What’s more, the researchers showed that restoring SNX27 in Down syndrome mice improves cognitive function and behavior.

“In the brain, SNX27 keeps certain receptors on the cell surface—receptors that are necessary for neurons to fire properly,” said Huaxi Xu, Ph.D., Sanford-Burnham professor and senior author of the study. “So, in Down syndrome, we believe lack of SNX27 is at least partly to blame for developmental and cognitive defects.”

SNX27’s role in brain function

Xu and colleagues started out working with mice that lack one copy of the snx27 gene. They noticed that the mice were mostly normal, but showed some significant defects in learning and memory. So the team dug deeper to determine why SNX27 would have that effect. They found that SNX27 helps keep glutamate receptors on the cell surface in neurons. Neurons need glutamate receptors in order to function correctly. With less SNX27, these mice had fewer active glutamate receptors and thus impaired learning and memory.

SNX27 levels are low in Down syndrome

Then the team got thinking about Down syndrome. The SNX27-deficient mice shared some characteristics with Down syndrome, so they took a look at human brains with the condition. This confirmed the clinical significance of their laboratory findings—humans with Down syndrome have significantly lower levels of SNX27.

Next, Xu and colleagues wondered how Down syndrome and low SNX27 are connected—could the extra chromosome 21 encode something that affects SNX27 levels? They suspected microRNAs, small pieces of genetic material that don’t code for protein, but instead influence the production of other genes. It turns out that chromosome 21 encodes one particular microRNA called miR-155. In human Down syndrome brains, the increase in miR-155 levels correlates almost perfectly with the decrease in SNX27.

Xu and his team concluded that, due to the extra chromosome 21 copy, the brains of people with Down syndrome produce extra miR-155, which by indirect means decreases SNX27 levels, in turn decreasing surface glutamate receptors. Through this mechanism, learning, memory, and behavior are impaired.

Restoring SNX27 function rescues Down syndrome mice

If people with Down syndrome simply have too much miR-155 or not enough SNX27, could that be fixed? The team explored this possibility. They used a noninfectious virus as a delivery vehicle to introduce new human SNX27 in the brains of Down syndrome mice.

“Everything goes back to normal after SNX27 treatment. It’s amazing—first we see the glutamate receptors come back, then memory deficit is repaired in our Down syndrome mice,” said Xin Wang, a graduate student in Xu’s lab and first author of the study. “Gene therapy of this sort hasn’t really panned out in humans, however. So we’re now screening small molecules to look for some that might increase SNX27 production or function in the brain.”

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This research was funded by the U.S. National Institutes of Health (National Institute on Aging grants R01AG038710, R01AG021173, R01AG030197, R01AG044420; National Institute of Neurological Disorders and Stroke grants R01NS046673, P30NS076411; Eunice Kennedy Shriver National Institute of Child Health & Human Development grant P01HD29587; National Institute of Environmental Health Sciences grant P01ES016738), Alzheimer’s Association, American Health Assistance Foundation, National Natural Science Foundation of China, 973 Prophase Project, Natural Science Funds for Distinguished Young Scholar of Fujian Province, Program for New Century Excellent Talents in Universities,  Fundamental Research Funds for the Central Universities, and Fok Ying Tung Education Foundation.

Original paper:

Wang, X., Zhao, Y., Zhang, X., Badie, H., Zhou, Y., Mu, Y., Loo, L., Cai, L., Thompson, R., Yang, B., Chen, Y., Johnson, P., Wu, C., Bu, G., Mobley, W., Zhang, D., Gage, F., Ranscht, B., Zhang, Y., Lipton, S., Hong, W., & Xu, H. (2013). Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down’s syndrome Nature Medicine DOI: 10.1038/nm.3117

Press coverage:

Down’s syndrome ‘linked to brain protein loss’
BBC, March 24, 2013

Down syndrome’s molecular cause found
U-T San Diego, March 24, 2013

ResearchBlogging.org

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Heather Buschman, Ph.D.

Heather was a Sanford-Burnham Communications staff member.

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48 Comments

    • Heather Buschman, Ph.D. on

      Hi Keith,

      That’s a very good question. Down syndrome and Alzheimer’s do share some molecular similarities. People with Down syndrome are at especially high risk for Alzheimer’s. Dr. Xu and his group are now studying the role of SNX27 in Alzheimer’s.

      Best,
      Heather

  1. Travis Wells on

    This is really impressive. What sort of hurdles must be cleared in order to go forward into human testing, and I suppose I mean both ethically and functionally?

    • Heather Buschman, Ph.D. on

      Hi Travis,

      Thanks for your comment. We’re a long way from human testing. First of all, the researchers used a gene therapy technique to administer SNX27 in this mouse model of Down syndrome and that is unlikely to work in humans. So now they are using high-throughput screening platforms available here at Sanford-Burnham to sift through hundreds of thousands of chemical compounds to find one (or a few) that boost SNX27 function or its downstream effects. Once they find a promising compound, it must be validated in model organisms and tested for toxicity. Only then will the potential therapy even begin the long process of clinical trials in humans. In short, it will take many years and a lot of funding.

      Best,
      Heather

      • Thanks so much for the breakthrough.

        What does it mean ‘many years’? the article said it may not help children much older than 10. What about today’s young children?

        • Heather Buschman, Ph.D. on

          Hi Eyal,

          At this point in the research, we don’t even yet have a chemical compound that influences SNX27 function. Once Dr. Xu and colleagues find one, it will still take about 10 years to validate and test it in model organisms, then begin the long process of clinical trials in humans. All that is necessary before FDA approval of a Down syndrome therapy is achieved.

          Best,
          Heather

  2. This is so amazing. And while it may be too late for my son … think of the countless children that wouldn’t be aborted if a cure (or help) were available. Hurry! and thank you.

    • That sounds like I aborted my son … I didn’t. I just meant that he may be too old to benefit from this if the science behind it takes years to develop.

  3. Luke Lazatin on

    First of all, this is just beautiful — both on its social and scientific implications.

    How exactly does SNX27 interact with these receptors, though? How was treatment in mice administered?

    • Heather Buschman, Ph.D. on

      Hi Luke,

      Thanks for your comment and questions! SNX27 is a trafficking protein, meaning that it helps proteins get where they need to be in a cell. Proteins that are expressed on the outer surface of the cell’s membrane are frequently recycled out onto the membrane, back inside the cell, and back out to the membrane. SNX27 interacts with glutamate receptors through its PDZ domain, recycling them back to the cell membrane, where the receptors can receive the signals necessary for neurons to function properly. Thus, low SNX27 = low glutamate receptors on cell surfaces = poor neuron firing = impaired learning and memory in Down syndrome.

      As for the treatment in the Down syndrome mouse model, the researchers used a noninfectious virus to deliver human SNX27 complementary DNA to the hippocampus. That technique repaired cognitive and synaptic deficits in the mouse model. However, it’s a tricky technique that’s not likely to pan out in humans. That’s why this research team is now looking for other ways to boost SNX27 or its downstream effects, or inhibit SNX27’s inhibitor. If they find a chemical compound that can do that and it passes all the efficacy and safety hurdles necessary for FDA approval, we could potentially see a therapy that improves learning and memory in Down syndrome. Unfortunately, that may take up to a decade and many millions of dollars.

      Best,
      Heather

  4. Dr. Bushman,
    When you say that the gene-therapy technique used is unlikely to work in humans — is that comment due to the fact that gene therapy in general has not had great success, or were you referring to the particular therapy that the researchers used? (If it’s the former, I’d be interested in furthering that part of the discussion.)
    My 6-year-old has down syndrome and I promote/write about science research for a living, so this news is interesting to me from several perspectives.

    Christian

    • Heather Buschman, Ph.D. on

      Hi Christian,

      Great question. The answer is both – gene therapy in general hasn’t really worked for many reasons and the same is likely to be true here. Not only was this a gene therapy technique (giving back the missing gene), it also uses a virus as a delivery vehicle. The virus itself is engineered to be non-infectious, but there would still be many safety concerns with injecting a virus into a brain. To achieve FDA approval, in most cases the benefit of a potential therapy has to far outweigh any possible negative side effects.

      As always, more research is needed!

      Best,
      Heather

  5. angela delossantos on

    When ever I see “MEMORY” in any article it makes me stop and read the whole thing. I have Epilepsy and this has caused memory problems. I have tried numerous things and medications. When there is a new pill I hear of, its either not for me or its the same as another I’ve already tried. The surgery to remove the part of the brain that causes the seizures, also can not be done because they come from both sides. Is there ANYTHING I can do to improve my memory? Please help

  6. Wow, imagine how this could improve the lives of people with Downs Syndrome and help them to gain more independence and abilities. I am continually amazed by the advances we are making in the medical field. Truly awesome.

  7. Hope is GREAT news! Currently young pregnant mothers are given very minimal positive outlook when a neonatal test indicates Down Syndrome. The high abortion rate following the diagnosis might be mitigated with a small amount of hope for a brighter future. Even ten years is not a life time lost. This discovery may well save lives long before a viable human delivery methodology is available. Hope is a powerful motivation for life!

  8. Hi Dr
    How long time do you think it is going to take to find a final solution for down syndrome patients based in this new discovery?
    Thanks
    Themis

    • Heather Buschman, Ph.D. on

      Hi Themis,

      It depends on what you mean by a “final solution.” It could take 10 years or more to find a safe and effective way to boost SNX27 or inhibit SNX27’s inhibitor. Even then, it remains to be seen what level of memory and learning improvement can be achieved – often times a treatment makes life a bit better, even without being a total “cure.”

      Heather

  9. My grandson reportedly has downs. EIP helped with sign language! I have found that he loves to respond to himself in a full body mirror! He is intrigued with his shadow when we are out in the sunshine! He also responds greatly to music! We also talk with him instead of at him! His favorite thing is to watch and sing along with “The Wiggles”! These are just a few of my observations. There are many more! I am just his “POP POP”!

  10. Pamela Donovan on

    I have a 26 year old daughter with Down Syndrome!
    I would like to know if she is likely to benefit from this research.

    • Heather Buschman, Ph.D. on

      Hi Pamela,

      If it continues to be successful, this research could take about 10 years to move from the lab to the clinic.

      Best of luck to you and your family!

      Heather

      • Gerardo Rojas Ossa on

        My 6 month old daughter has DS; I’m an engineer with strong University bonds,
        Is there any way we can help Drs. Wang, Xu, to complete their research?
        Can we add funds, or help by studying mathematical/stochastical models for the protein delivery?

        Thanks!

        Gerardo.

        • Patrick Bartosch
          Patrick Bartosch on

          Hi Gerardo,

          Thanks a lot for your comment and your interest in our research. If you’re interested in supporting this research, please visit sanfordburnham.org and click on “Make a Donation.” You can pick a research area to support.

          Thank you!

          Patrick

          • Gerardo Rojas Ossa on

            Sure thing I’ll do!

            Patrick, I’m visiting La Jolla on January; is there a possibility to go to the Institute and meet anyone of that team?
            It’s a long way from Santiago, Chile; and my wife wants it as much as I do. We know the importance that you give to your work and also that this as promising as it is may get into a dead end; but It’ll be great just to take 2 minutes from anyone on the team to talk, to thank you and bring a pic home of the guys that fight day to day on getting a brighter future to our children.

            All the best!

            Gerardo

  11. Could similar molecular cause explain learning and memory deficits with other syndromes and neurocognitive difficulties such as learning disabilities, ADHD ? Are there any practical immediate applications of this finding for parents of affected children? any other ways to increase brain glutamate receptors ? I cannot thank enough the research team for their work, and the blog to provide info to the general public.

  12. Stephanie Porter on

    This is nice to know, it was finally researched and figured out, now they need to do more for brain injury survivors { car accidents, annurysms, strokes, falling, sports, etc. }, I am really glad that this has been discovered though, this is great! You are on a roll to discover more about disabilities than ever! KEEP UP the GOOD work!

  13. Sergio Anides on

    This is a very promising study that may help improve the life of our children with Down Syndrome. You may want to consider to collect some funds via the internet. I’ve heard that some researchers are using it now for that purpose. I would contribute. Thanks to you and your team, I am really grateful for what you are doing.

  14. hi, this is such good news. Finally to know what the extra chromosome does to the brain and how it takes away rather than adding. My son is 33 and quite normal i8n many respects and some times people forget his limitaions.
    Is it possible to be kept informed about the progress of this research. I feel 10 years is better than never!!
    When you get to the stage of Clinical Trials, we would be very interested Bharat, our Son, participating.
    Could you let me know the website where I can monitor the progress of this research and keep up to date with its progress and any side effects introducing the protein might have.
    thanks and best regards,
    anubha

  15. i believe my 31 yr old son in law has downs. he has the eye and mouth features of downs. he has behavirol problems. cn you pls. tell me some of the problems that are assoicated to this in an adult that has gone undionosed?

  16. Hello,
    I have a 23 months daughter with Down Syndrome (low level). I would like to know if she can benefit from the research.
    Thanks

  17. Marsha Scheitlin on

    In another article that discussed the recent discovery about SNX27 and Down Syndrome,
    it was stated “If the mouse model is a good guide, such therapy should work in children almost up until puberty. Mice were tested for such abilities as learning how to run mazes. Those treated at the age of one month grew up to test normally, Xu said. A one-month-old mouse is comparable to a 10-year-old child when adjusted for lifespan, he said.

    Treatment on older mice didn’t work because their brain circuitry had become too fixed, Xu said.”
    http://www.utsandiego.com/news/2013/mar/24/down-syndrome-sanford-burnham-trisomy-21/

    Heather – you stated that it could be 10 years before a SNX inhibitor is available.
    10 – 10 = 0…..in other words, this particular therapy will probably not benefit any child living
    at this time. Please be honest with people and do not create false hope. That is cruel.

  18. vipin tyagi on

    Hello,
    I have a 12 months Son with Down Syndrome (low level). I would like to know if he can benefit from the research.
    Thanks

    • Patrick Bartosch
      Patrick Bartosch on

      Hello!

      At Sanford-Burnham, we conduct basic, early medical research. Our Down syndrome research is currently only tested in animal models. It will probably be a few years until it is ready to go to a patient. Keep following our blog to stay updated. Thanks!

  19. Dear Dr,
    We have a 17 years old son with Downs, Autism and severe learning disability. If this research works at least we sort 2 out 3 of his problems. Where we can hear more about these type of researches?

    • Patrick Bartosch
      Patrick Bartosch on

      Thank you for your comment and following our blog. To stay updated on our research, please continue reading Beaker and also check out our website at sanfordburnham.org.

  20. 1. What prevent from just delivering synthesized SNX27 to brain (by binding it with some other vehicle to go through brain-blood barrier)?
    2. You reiterate >10 years of validating and testing, but in reality many drugs reached the market much faster. I understand that you don’t want to give false expectations, however please understand also that this research is not a pure theory, it relates to lives of so many people. Even not fully tested drug may be chosen by many, if compared with a possibility to see his loved ones never benefiting from this medicine when it is available and already too late.

  21. Doctor, are you familiar with Soto’s syndrome? Similar chromosomal situation. Wondering if this strategy would also work in these cases? Keep up the great work. This seems like a giant step well taken. Looking forward to hearing more on this research.

  22. Dear Doctor, my son is a downsyndrom child, if it is recoverable, please tell me. I and my family is very thankful to you.

  23. Dear Sir, My Grandson 6 is having Down Syndrome (P21 transposed on P14). He is unable to speek and weak muscles. Please inform if any help is available.

  24. mangal bhagyawan bhagyawant on

    i have son of four years old. he have problem of down syndrom he hear 50%.he talk some words baba dada mamai bhavu didi please give me suggetion about that

  25. hi
    myself Preety ..an indian …having a 13yrs old downsyndrome male child. I want to know how can these kids be treated …n to what extent they become normal .If this treatment has such a miraculous results i want my baby to be normal.Is this treatment has been started on these kids or it yet to be start.and what will be the cost of this treatment…..

  26. Down syndrome is such a problem for the families who are coping with this. It just hampers the growth of the family on the whole. Will that day come come when medicine for this shall be available . My Salute for all those who are working for the cause.

  27. Jai Kishor Prasad on

    My son was born on 11th Nov 2011 with Down Syndrome. His condition is not so bad. We feel that if some medicine is invented though your research then it will be miracle for our life! We are keeping our fingers crossed for a positive result!

  28. I am a retired banker with commerce background. only thing I gather from the above article is that cause of downsyndrome features in such children have been finalized. Is there any treatment for such children or can I hope that such children will be cured in the time to come. My younger is son is a downsyndrome child with 25% IQ as informed by the hospital authorities. He is now 17 years old. I get apprehancsive about his well being after our death (Me and my wife). I want that he should be able to understand his rights so that he may lead his whole life comfortably after us.

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