{"id":452,"date":"2018-04-16T20:31:22","date_gmt":"2018-04-16T20:31:22","guid":{"rendered":"https:\/\/neuroepic.mcdb.lsa.umich.edu\/wp\/?page_id=452"},"modified":"2023-04-07T17:47:12","modified_gmt":"2023-04-07T17:47:12","slug":"17-neuroepigenetics-of-epilepsy","status":"publish","type":"page","link":"https:\/\/courses.lsa.umich.edu\/neuroepic\/17-neuroepigenetics-of-epilepsy\/","title":{"rendered":"Neuroepigenetics of Epilepsy"},"content":{"rendered":"\n<p class=\"has-text-align-center wp-block-paragraph\">Leila Eter \u201918 and Lauren Smith \u201918<\/p>\n\n\n\n<figure class=\"wp-block-embed is-type-rich is-provider-spotify wp-block-embed-spotify wp-embed-aspect-21-9 wp-has-aspect-ratio\"><div class=\"wp-block-embed__wrapper\">\n<iframe title=\"Spotify Embed: 17. Neuroepigenetics of Epilepsy\" style=\"border-radius: 12px\" width=\"100%\" height=\"152\" frameborder=\"0\" allowfullscreen allow=\"autoplay; clipboard-write; encrypted-media; fullscreen; picture-in-picture\" loading=\"lazy\" src=\"https:\/\/open.spotify.com\/embed\/episode\/0F9xEhZIawpSDjYd8t8EM6?si=0WvuyBO7SsC4BRHUpSo1EA&#038;utm_source=oembed\"><\/iframe>\n<\/div><\/figure>\n\n\n\n<p class=\"wp-block-paragraph\"><span style=\"font-weight: 400;\">When we visit the doctor with a medical concern we typically expect to leave with a prescription. One pill in the morning, one at night, and some water and nourishing foods to fuel the body for healing. But when Hollywood producer Jim Abrahams took his one year old son, Charlie, to Johns Hopkins in 1993 for treatment of epilepsy, he was prescribed\u2026 high fat diet? Doctors prescribing fat? It seems a little bit counterintuitive, but to Jim\u2019s surprise, this once-controversial treatment stopped his son\u2019s crippling seizures altogether in only three days, a feat that several medications and surgical attempts had failed to accomplish (Baruchin, 2008)! Charlie is one of about 2.5 million people in the U.S. l<\/span>iving with epilepsy, one-third of whom also do not respond to anti-seizure medications (Holland, 2014). Charlie remained on the diet for five years, and has since been seizure free. The high-fat diet that miraculously stopped Charlie\u2019s seizures is now a standard treatment for epilepsy patients. But this diet and its unexpected success raises a flustering question for scientists: How on earth can fat rewire a brain to prevent seizures?<br><span style=\"font-weight: 400;\">To begin to answer this question, let\u2019s zoom in to a single cell in Charlie\u2019s brain. In the nucleus of this cell you\u2019ll find DNA. This DNA contains the instructions for Charlie\u2019s body in the form of \u201cgenes.\u201d Each cell contains his entire copy of genes, including the brain genes. But if you look a little bit closer, you\u2019ll notice that there are other molecules interacting with and modifying these genes. These molecules act like signals to the cell\u2019s machinery, telling it when to turn a gene \u201con\u201d or \u201coff\u201d. These modifications are added to the DNA, but they never actually change the DNA sequence. The Greek prefix \u201cepi\u201d means on, above, or nearby, so these modifications are called \u201cepigenetic,\u201d and they allow the cell to turn genes on or off in response to its environment. As the bridge between genes and environment, epigenetics is a promising explanation in solving the mystery of how the high fat diet can prevent seizures. This opened up a door into a new world of epilepsy research, one that would now focus<\/span>heavily on better understanding the role of the environment and not just genes in epilepsy and its treatment.<br><span style=\"font-weight: 400;\">Scientists have found that one way in which epigenetics is involved in epilepsy is DNA methylation. We can think of our genes as street traffic. When genes are \u201con\u201d, they have a green light. DNA methylation is a tag that is added to DNA that acts like a red light at a stoplight, turning the gene \u201coff\u201d (Figure 1). Interestingly, studies show that the DNA methylation tags are different in the brains of epileptic rats. In a recent study, scientists found too many red lights in the brains of epileptic rats when they should have been green lights, so genes that should have been \u201con\u201d were now \u201coff\u201d (Kobow et. al, 2013). So now that there are known epigenetic differences in patients with epilepsy, how can this information be used to help treat real people like Charlie and the other 2.5 million people suffering from epilepsy?<\/span><br><span style=\"font-weight: 400;\">The scientists\u2019 solutio<\/span>n? High fat diet! One recent study looked into the possibility that DNA methylation might play a role in the high fat diet\u2019s effect of preventing epilepsy. Scientists wanted to know how they could turn red lights back into green lights to help these patients. They haven\u2019t found a connection between high fat and the methylation tags of specific genes, but they are working towards answers.<br><\/p>\n\n\n<div class=\"wp-block-image\">\n<figure class=\"aligncenter\"><img loading=\"lazy\" decoding=\"async\" width=\"942\" height=\"339\" src=\"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-content\/uploads\/sites\/16\/2018\/04\/DNA-methylation.png\" alt=\"\" class=\"wp-image-489\" srcset=\"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-content\/uploads\/sites\/16\/2018\/04\/DNA-methylation.png 942w, https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-content\/uploads\/sites\/16\/2018\/04\/DNA-methylation-300x108.png 300w, https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-content\/uploads\/sites\/16\/2018\/04\/DNA-methylation-768x276.png 768w, https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-content\/uploads\/sites\/16\/2018\/04\/DNA-methylation-604x217.png 604w\" sizes=\"auto, (max-width: 942px) 100vw, 942px\" \/><\/figure>\n<\/div>\n\n\n<h5 class=\"wp-block-heading\"><span style=\"font-weight: 400;\">Figure 1: DNA Methylation, (modified from <\/span><a href=\"https:\/\/atlasofscience.org\/dna-methylation-markers-in-colorectal-cancer-state-of-the-art\/\"><span style=\"font-weight: 400;\">https:\/\/atlasofscience.org\/dna-methylation-markers-in-colorectal-cancer-state-of-the-art\/<\/span><\/a><span style=\"font-weight: 400;\">)<\/span><\/h5>\n\n\n\n<p class=\"wp-block-paragraph\"><span style=\"font-weight: 400;\">The same diet that stopped Charlie\u2019s seizures was able to fix the methylation tags in epileptic rats and turn their red lights back into green lights (Kobow et. al, 2013). At the present time, it is thought that the high-fat diet causes an increase in a molecule called adenosine. We can think of adenosine molecules as people in a parade through the streets. Even though the traffic lights had been red previously, turning the genes \u201coff\u201d via methylation tags, this parade effectively turns the traffic light green again, allowing traffic to move regardless of the light\u2019s instructions. Therefore, genes that were \u201coff\u201d are now back \u201con\u201d again. This can help return high levels of methylation tags back to healthy levels in epileptic patients. In another recent study, researchers fed epileptic mice a high-fat diet and then reversed their diet back to normal to observe the long term effects on their brains. They saw that 2 months later, there were still less methylation tags in the part of the brain affected by epilepsy, and the animals had fewer seizures even up to six months after (Lusardi et. al, 2015). This shows that not only can the high-fat diet improve epilepsy treatment, but also that these effects can be long-lasting. These findings are consistent with Charlie\u2019s experience, as he no longer eats a high-fat diet and has not had a seizure in over two decades. Eventually, this work could translate into patients not having to consistently maintain this high fat diet that comes with many other health consequences.<\/span><br><span style=\"font-weight: 400;\">Like DNA methylation, microRNAs (miRNA) are another likely epigenetic culprit in epilepsy. miRNAs are molecules that are like construction, so even if the light is green, you still can\u2019t get where you need to go, causing the gene to be effectively \u201coff\u201d. Scientists have found that there are more miRNAs in the epileptic rat brain than there should be, so more genes are blocked by this construction, turning more genes \u201coff\u201d (Gorter et. al, 2013). One of the miRNAs that scientists found to be upregulated in epilepsy is miR-134 . These scientists\u2019 findings suggest that miR-134 is partially responsible for causing seizures to recur.<\/span><br><span style=\"font-weight: 400;\">Other potential avenues of treatment taking advantage of these different epigenetic features are also being investigated. The same group that found miR-134 to be increased in epilepsy found that a synthetic molecule called an \u201cantagomir\u201d acts like a detour through the construction, building a different path for the gene so that it can be turned \u201con\u201d again. This antagomir can block miR-134 and reverse the effects of miR-134. Cells typically show more wear and tear in the brain of a patient with epilepsy, with more cells dying and becoming disorganized. However, upon providing a detour for the DNA by treating with the antagomir, they found the brains were healthier, with less neuronal damage and cell death. Treating with this antagomir also caused a decrease in the number of seizures within a two week period, and there was even an increase in the number of seizure-free days still at two months after treatment (Jimenez-Mateos et. al, 2012).<\/span><br><span style=\"font-weight: 400;\">Let\u2019s return to Charlie now, and we can see that the distinction between \u201cnature\u201d and \u201cnurture\u201d has become quite fuzzy. Conditions like Charlie\u2019s epilepsy are ones in which your environment, for example what you eat, can directly affect your DNA and how it relays messages throughout the cells in your body. Patients like Charlie have different methylation tags on their DNA turning traffic lights red as well as more miR-134 causing construction, which both work to turn genes \u201coff\u201d. In acknowledging the intertwining factors that impact diseases like epilepsy, we can begin to target the \u201cnurture\u201d using what \u201cnature\u201d we do know.<\/span><br>&nbsp;<\/p>\n\n\n\n<p class=\"has-text-align-center wp-block-paragraph\">References<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><span style=\"font-weight: 400;\">Lusardi, T. A., Akula, K. K., Coffman, S. Q., Ruskin, D. N., Masino, S. A., &amp; Boison, D. (2015). <\/span><span style=\"font-weight: 400;\">Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats. <\/span><i><span style=\"font-weight: 400;\">Neuropharmacology<\/span><\/i><span style=\"font-weight: 400;\">, <\/span><i><span style=\"font-weight: 400;\">99<\/span><\/i><span style=\"font-weight: 400;\">, 500\u2013509. <\/span><br><span style=\"font-weight: 400;\">Jimenez-Mateos, E. M., Engel, T., Merino-Serrais, P., McKiernan, R. C., Tanaka, K., Mouri, G., <\/span><span style=\"font-weight: 400;\">Henshall, D. C. (2012). Silencing microRNA-134 produces neuroprotective and <\/span><span style=\"font-weight: 400;\">prolonged seizure-suppressive effects. <\/span><i><span style=\"font-weight: 400;\">Nature Medicine<\/span><\/i><span style=\"font-weight: 400;\">, <\/span><i><span style=\"font-weight: 400;\">18<\/span><\/i><span style=\"font-weight: 400;\">(7), 1087\u20131094. <\/span><br><span style=\"font-weight: 400;\">Baruchin, A. (2008, May 06). Evidence a High-Fat Diet Works to Treat Epilepsy. Retrieved&nbsp;<\/span><span style=\"font-weight: 400;\">March 20, 2018, from http:\/\/www.nytimes.com\/2008\/05\/06\/health\/research\/06epil.html<\/span><br><span style=\"font-weight: 400;\">Holland, K. (2014, October). Epilepsy: Statistics, Facts and You. Retrieved March 20, 2018,<\/span><span style=\"font-weight: 400;\">from <\/span><a href=\"https:\/\/www.healthline.com\/health\/epilepsy\/facts-statistics-infographic\"><span style=\"font-weight: 400;\">https:\/\/www.healthline.com\/health\/epilepsy\/facts-statistics-infographic<\/span><\/a><br><span style=\"font-weight: 400;\">Kobow, K., Kaspi, A., Harikrishnan, K. N., Kiese, K., Ziemann, M., Khurana, I., Fritzsche, I.,<\/span><span style=\"font-weight: 400;\">&nbsp;Hauke, J., Hahnen, E., Coras, R., Muhlebner, A., El-Osta, A., Blumcke, I. (2013). Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. <\/span><i><span style=\"font-weight: 400;\">Acta Neuropathologica, 126(5)<\/span><\/i><span style=\"font-weight: 400;\">, 741-756.<\/span><br><span style=\"font-weight: 400;\">Gorter, J.A., Iyer, A., White, I., Colzi, A., Van Vliet, E.A., Sisodiya, S., Aronica, E. (2013).&nbsp;<\/span><span style=\"font-weight: 400;\">Hippocampal subregion-specific microRNA expression during epileptogenesis in experimental temporal lobe epilepsy. <\/span><i><span style=\"font-weight: 400;\">Neurobiology of Disease, 62,<\/span><\/i><span style=\"font-weight: 400;\"> 508-520.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Leila Eter \u201918 and Lauren Smith \u201918 When we visit the doctor with a medical concern we typically expect to leave with a prescription. One pill in the morning, one at night, and some water and nourishing foods to fuel the body for healing. But when Hollywood producer Jim Abrahams took his one year old&hellip; <a class=\"more-link\" href=\"https:\/\/courses.lsa.umich.edu\/neuroepic\/17-neuroepigenetics-of-epilepsy\/\">Continue reading <span class=\"screen-reader-text\">Neuroepigenetics of Epilepsy<\/span><\/a><\/p>\n","protected":false},"author":33,"featured_media":2080,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-452","page","type-page","status-publish","has-post-thumbnail","hentry","entry"],"_links":{"self":[{"href":"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-json\/wp\/v2\/pages\/452","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-json\/wp\/v2\/users\/33"}],"replies":[{"embeddable":true,"href":"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-json\/wp\/v2\/comments?post=452"}],"version-history":[{"count":1,"href":"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-json\/wp\/v2\/pages\/452\/revisions"}],"predecessor-version":[{"id":2677,"href":"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-json\/wp\/v2\/pages\/452\/revisions\/2677"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-json\/wp\/v2\/media\/2080"}],"wp:attachment":[{"href":"https:\/\/courses.lsa.umich.edu\/neuroepic\/wp-json\/wp\/v2\/media?parent=452"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}