Science<\/a>\u00a0in July, scientists at Children\u2019s Medical Center Research Institute at UT Southwestern (CRI) explained why babies born with the deficiency suffer from severe neurological impairment, and they have identified a potential strategy to intervene.<\/p>\nArticle continues below this ad<\/p>\n
Developing a biosensor<\/p>\n
Sam McBrayer\u2019s interest in metabolism, or chemical changes in the human body, began during his training in biochemistry, when he realized he wanted to pursue questions related to human physiology and disease. This fascination became the basis of his lab\u2019s research, which looks at the development of brain tumors and symptoms associated with metabolic disorders.<\/p>\n
Eventually, that interest guided him to Alpha-ketogluterate (\u03b1KG), a type of small molecule capable that plays an important role in controlling which genes are turned on or off, explained McBrayer, an assistant professor at CRI and the study leader.\u00a0<\/p>\n
Researchers didn\u2019t understand how \u03b1KG is transported to the nucleus, a cell\u2019s DNA-containing control center. Alex\u00a0Sternisha, a former graduate student of McBrayer and lead author on the study, built a tool to find out.<\/p>\n
Sternisha took a protein from a bacteria that could recognize \u03b1KG and modified it to work in human cells. He also linked it to a glowing green protein, so that the more \u03b1KG was within a cell, the brighter it would glow.\u00a0<\/p>\n
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\u201cIt’s been kind of a holy grail in the field to have a way to measure alpha ketoglutarate in the nucleus,\u201d McBrayer said. \u201cNo one’s been able to do that.\u201d<\/p>\n
GPT2\u2019s role in gene expression<\/p>\n
Using the newly developed tool, researchers discovered that an enzyme known as GPT2 is responsible for producing \u03b1KG.\u00a0<\/p>\n
![\"Artist's]()
<\/p>\n
Artist’s rendering of the production and transfer of \u03b1KG from the mitochondria\u00a0to the nucleus\u00a0by sequential activities of GPT2 and SLC25A11.\u00a0<\/p>\n
Melissa Logies for CRI<\/p>\n
\u201cWe’ve known about this enzyme for probably 80 years,\u201d said Dr. Ralph DeBerardinis, the director of UT Southwestern Medical Center’s Eugene McDermott Center for Human Growth and Development, and a co-author on the study. Nobody would have ever guessed that it helped regulate gene activation by producing \u03b1KG, he said.<\/p>\n
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Mutations in the gene for GPT2 can deactivate it, McBrayer said, leading to less \u03b1KG being produced.\u00a0This results in many genes important for brain development to remain unactivated.<\/p>\n
\u201cWhen that gene is mutated,\u00a0patients are afflicted with a broad spectrum of different neurological symptoms,\u201d McBrayer said. These include severe intellectual disabilities, issues with movement and failure or delays in developing speech and language.\u00a0<\/p>\n
As there is no treatment for the disease, there\u2019s a strong incentive to develop strategies that can help alleviate patients\u2019 symptoms,\u00a0McBrayer said.<\/p>\n
A potential treatment<\/p>\n
The new research suggests \u03b1KG supplementation at birth might help diminish disease progression.<\/p>\n
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To test their theory, McBrayer and Dr. Eric Morrow, the Mencoff Family professor of biology at Brown University, tested the treatment on mice without the GPT2 protein. They found that by supplementing these mice with \u03b1KG from birth, newborn mice were able to maintain their body weight. This indicated the treatment was effective in addressing one of the disease\u2019s characteristics.<\/p>\n
![\"From]()
<\/p>\n
From left, Haocheng Li, Dr. Alex Sternisha\u00a0and Sam McBrayer, assistant professor in Children\u2019s Medical Center Research Institute at UT Southwestern (CRI).<\/p>\n
CRI<\/p>\n
DeBerardinis said \u03b1KG is a promising candidate for treatment, but he said a chemically modified version would likely be needed to prevent it from being broken down by the body before it reaches the brain.<\/p>\n
\u201cI think the key gap that we need to address now is how you can give this chemically modified version of \u03b1KG very early in life and continuously to try and alleviate some of the damaging effects that depletion of this molecule has in the developing brain,\u201d said McBrayer. \u201cThis includes simple questions related to formulation, frequency of dosing, and route of administration.\u201d<\/p>\n
Researchers also have yet to identify the time window in which supplementation needs to occur for it to work.\u00a0<\/p>\n
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In a press release, Morrow expressed his excitement regarding the development of potential treatments to help patients with GPT2 deficiencies. The researchers will continue to test their treatment in animal studies, and McBrayer said they intend to advance it to clinical trials.<\/p>\n
\u201cIt\u2019s a rare disorder,\u201d said McBrayer, explaining how it was discovered within the past decade. But their research, he said, \u201chas directed increased attention towards diagnosis of the disorder that will ultimately lead to appreciation of the broader prevalence of this disease.\u201d<\/p>\n
Niamh Ordner is a science reporting fellow at The Dallas Morning News. Her fellowship is supported by the University of Texas at Dallas. The News makes all editorial decisions. \u00a0<\/p>\n","protected":false},"excerpt":{"rendered":"From left, Sam McBrayer, assistant professor in Children\u2019s Medical Center Research Institute at UT Southwestern (CRI), with\u00a0Haocheng Li…\n","protected":false},"author":2,"featured_media":392648,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[9],"tags":[102,104,103,858,2220,138183,88971],"class_list":["post-392647","post","type-post","status-publish","format-standard","has-post-thumbnail","category-dallas","tag-dallas","tag-dallas-headlines","tag-dallas-news","tag-research","tag-science","tag-scientific-research","tag-tp-science-and-medicine"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/posts\/392647","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/comments?post=392647"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/posts\/392647\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/media\/392648"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/media?parent=392647"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/categories?post=392647"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/us-tx\/wp-json\/wp\/v2\/tags?post=392647"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}