{"id":137918,"date":"2024-12-17T05:01:57","date_gmt":"2024-12-16T22:01:57","guid":{"rendered":"https:\/\/hotvideos24.online\/?p=137918"},"modified":"2024-12-17T05:01:57","modified_gmt":"2024-12-16T22:01:57","slug":"protein-loss-triggers-molecular-changes-linked-to-rett-syndrom","status":"publish","type":"post","link":"https:\/\/hotvideos24.online\/?p=137918","title":{"rendered":"Protein Loss Triggers Molecular Changes Linked to Rett Syndrom"},"content":{"rendered":"<p> <script async src=\"https:\/\/pagead2.googlesyndication.com\/pagead\/js\/adsbygoogle.js?client=ca-pub-3711241968723425\"\r\n     crossorigin=\"anonymous\"><\/script>\r\n<ins class=\"adsbygoogle\"\r\n     style=\"display:block\"\r\n     data-ad-format=\"fluid\"\r\n     data-ad-layout-key=\"-fb+5w+4e-db+86\"\r\n     data-ad-client=\"ca-pub-3711241968723425\"\r\n     data-ad-slot=\"7910942971\"><\/ins>\r\n<script>\r\n     (adsbygoogle = window.adsbygoogle || []).push({});\r\n<\/script><br \/>\n<\/p>\n<div>\n<p><strong>Summary: <\/strong>Researchers have uncovered how loss of the MeCP2 protein triggers early molecular changes leading to Rett syndrome, a severe neurological disorder. By studying adult mice, they demonstrated that MeCP2 loss disrupts gene expression well before measurable neurological deficits arise.<\/p>\n<p>The findings show that MeCP2 dysfunction leads to both increased and decreased expression of genes critical for neuronal function. This research identifies a key window where molecular events occur, offering potential targets for early intervention in Rett syndrome.<\/p>\n<p><strong>Key Facts<\/strong><\/p>\n<ul class=\"wp-block-list\">\n<li><strong>Early Gene Changes:<\/strong> Loss of MeCP2 leads to immediate gene expression dysregulation, affecting hundreds of genes.<\/li>\n<li><strong>Neuronal Impact:<\/strong> Dysregulated genes are linked to neuronal function, causing downstream circuit-level deficits.<\/li>\n<li><strong>Therapeutic Window:<\/strong> The study reveals a time frame between molecular changes and neurological symptoms, enabling early intervention opportunities.<\/li>\n<\/ul>\n<p><strong>Source: <\/strong>Baylor College of Medicine<\/p>\n<p><strong>Researchers at\u00a0Baylor College of Medicine,\u00a0Jan and Dan Duncan Neurological Research Institute\u00a0(Duncan NRI) at Texas Children\u2019s Hospital and collaborating institutions have gained new insights into the molecular changes leading to Rett syndrome, a severe neurological disorder caused by mutations in the\u00a0<em>MeCP2<\/em>\u00a0gene encoding methyl-CpG binding protein 2 (MeCP2). <\/strong><\/p>\n<p>The team reports in the journal\u00a0<em>Neuron<\/em>\u00a0that loss of\u00a0<em>MeCP2<\/em>\u00a0in adulthood causes immediate progressive dysregulation of hundreds of genes \u2013 some are activated while others are suppressed \u2013 and these changes occur well before any measurable deficiencies in neurological function.<\/p>\n<figure class=\"wp-block-image size-full\"><picture fetchpriority=\"high\" decoding=\"async\" class=\"wp-image-107096\"><source type=\"image\/webp\" srcset=\"https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence.jpg.webp 1200w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-300x200.jpg.webp 300w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-770x513.jpg.webp 770w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-1155x770.jpg.webp 1155w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-370x247.jpg.webp 370w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-293x195.jpg.webp 293w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-150x100.jpg.webp 150w\" sizes=\"(max-width: 1200px) 100vw, 1200px\"\/><img fetchpriority=\"high\" decoding=\"async\" width=\"1200\" height=\"800\" src=\"https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence.jpg\" alt=\"This show neurons.\" srcset=\"https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence.jpg 1200w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-300x200.jpg 300w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-770x513.jpg 770w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-1155x770.jpg 1155w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-370x247.jpg 370w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-293x195.jpg 293w, https:\/\/neurosciencenews.com\/files\/2024\/12\/molecular-change-rett-syndrom-neurosicence-150x100.jpg 150w\" sizes=\"(max-width: 1200px) 100vw, 1200px\"\/> <\/picture><figcaption class=\"wp-element-caption\">Many of the genes dysregulated due to MeCP2 loss are directly related to neuronal function, and some of these genes have been directly shown to modulate MeCP2-driven disease. Credit: Neuroscience News<\/figcaption><\/figure>\n<p>The MeCP2 protein is most highly expressed in neurons \u2013 brain cells where, like an orchestra conductor, MeCP2 directs the expression of hundreds of genes.<\/p>\n<p>When mutations produce a nonfunctional MeCP2 protein, the conductor is no longer present to direct the harmonious expression of genes needed for normal brain function. The resulting discord in gene expression leads to Rett syndrome.<\/p>\n<p>\u201cIn the current study, our goal was to better understand the molecular changes that occur upon loss of MeCP2 function. Previous research has attempted to do this by studying the condition in animals presenting severe symptoms of the disorder.<\/p>\n<p>\u201cHowever, it has been difficult to separate the molecular changes caused by loss of\u00a0<em>MeCP2<\/em>\u00a0from those occurring during development or secondary to sick neurons,\u201d said first author\u00a0Dr. Sameer S. Bajikar, who was working in the\u00a0lab\u00a0of\u00a0Dr. Huda Zoghbi\u00a0during most of this project.<\/p>\n<p>Bajikar is currently an assistant professor at the University of Virginia.<\/p>\n<p>During the development of an organism, many genes are expressed and repressed \u2013 many \u2018harmonies\u2019 are played simultaneously creating a complex composition. It can be challenging to distinguish the harmonies emerging from the lack of\u00a0<em>MeCP2<\/em>\u00a0from the others.<\/p>\n<p>The researchers looked for a way to simplify the complex harmonies so they would be able to identify those coming from\u00a0<em>MeCP2<\/em>\u00a0dysregulation. Knowing that\u00a0<em>MeCP2<\/em>\u00a0function is required throughout life, that the\u00a0<em>MeCP2<\/em>\u00a0director is active during the entire life of an organism, inspired the researchers to focus on adult life, a time past development, when there are no more developmental compositions playing.<\/p>\n<p>\u201cWe conditionally deleted\u00a0<em>Mecp2\u00a0<\/em>in adult mice, which reproduces all the characteristic deficits and premature death observed in male animals in which the\u00a0<em>Mecp2<\/em>\u00a0is deleted from conception. Then, we systematically assessed gene expression, as well as events involved in gene expression regulation, at multiple times after adult loss of\u00a0<em>Mecp2<\/em>,\u201d Bajikar said.<\/p>\n<p>\u201cWe found that adult deletion of\u00a0<em>Mecp2<\/em>\u00a0changes the expression of many genes very early after\u00a0<em>Mecp2<\/em>\u00a0loss, some genes\u2019 expression was increased while others reduced. These gene expression changes became more robust over time and mirrored those of the\u00a0<em>Mecp2<\/em>\u00a0germline knockout mice.<\/p>\n<p>\u201cThese data revealed a molecular cascade that drives disease independent of any developmental contributions \u2013 we were able to identify the \u2018harmonies\u2019 coming from\u00a0<em>MeCP2<\/em>\u00a0dysregulation.\u201d<\/p>\n<p>The team also found that both the persistently up- and down-regulated genes were highly tagged with methyl chemical groups. Cytosine methylation within and near genes regulates their expression.<\/p>\n<p>Many of the genes dysregulated due to\u00a0<em>MeCP2<\/em>\u00a0loss are directly related to neuronal function, and some of these genes have been directly shown to modulate\u00a0<em>MeCP2<\/em>-driven disease.<\/p>\n<p>A key finding from this study is that neuronal circuit-level deficits occurred after gene expression dysregulation, suggesting\u00a0<em>Mecp2<\/em>\u00a0deletion leads to bidirectional dysregulation of gene expression first and that in turn contributes to reduced neuronal function.<\/p>\n<p>\u201cOur data also provide a resource to identify genes dysregulated downstream of\u00a0<em>MeCP2<\/em>, but upstream of circuit-level deficits and are critical for proper neuronal function. These genes warrant further study,\u201d said Zoghbi, Distinguished Service Professor at\u00a0Baylor, director of the Duncan NRI and a\u00a0Howard Hughes Medical Institute\u00a0investigator.<\/p>\n<p>\u201cLastly, our data demonstrate that there is a window of time when molecular events downstream of\u00a0<em>MeCP2<\/em>\u00a0are occurring, but before overt physiological consequences are measurable,\u201d Zoghbi said.<\/p>\n<p>\u201cInvestigating specific changes during this window will be important for fully characterizing the trajectory of molecular events leading to Rett syndrome.\u201d<\/p>\n<p>Jian Zhou, Ryan O\u2019Hara, Harini P. Tirumala, Mark A. Durham, Alexander J. Trostle, Michelle Dias, Yingyao Shao, Hu Chen, Wei Wang, Hari K. Yalamanchili, Ying-Wooi Wan, Laura A. Banaszynski and Zhandong Liu also contributed to this work.<\/p>\n<p>The authors are affiliated with one of more of the following institutions: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital and UT Southwestern Medical Center, Dallas.<\/p>\n<p><strong>Funding: <\/strong>This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Development (F32HD100048, R01HD109239, U54HD083092), National Institute of Neurological Disorders and Stroke (R01NS057819, K99\/R00NS129963), National Institute of General Medical Sciences (R35GM124958), The Welch Foundation (I-2025), American Cancer Society (134230-RSG-20-043-01-DMC), Duncan NRI Zoghbi Scholar Award through Texas Children\u2019s Hospital, the International Rett Syndrome Foundation (4013) and the Howard Hughes Medical Institute.<\/p>\n<h2 class=\"wp-block-heading\">About this Rett syndrome and genetics research news<\/h2>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Author: <\/strong><a href=\"http:\/\/neurosciencenews.com\/cdn-cgi\/l\/email-protection#014673606268646d602f46747568647373647b4163626c2f646574\" target=\"_blank\" rel=\"noreferrer noopener\">Graciela Gutierrez<\/a><br \/><strong>Source: <\/strong><a href=\"https:\/\/bcm.edu\" target=\"_blank\" rel=\"noreferrer noopener\">Baylor College of Medicine<\/a><br \/><strong>Contact: <\/strong>Graciela Gutierrez \u2013 Baylor College of Medicine<br \/><strong>Image: <\/strong>The image is credited to Neuroscience News<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Original Research: <\/strong>Open access.<br \/>\u201c<a href=\"https:\/\/dx.doi.org\/10.1016\/j.neuron.2024.11.006\" target=\"_blank\" rel=\"noreferrer noopener\">Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that precede neurological dysfunction and inform pathogenic cascade<\/a>\u201d by Sameer S. Bajikar et al. <em>Neuron<\/em><\/p>\n<hr class=\"wp-block-separator has-text-color has-pale-cyan-blue-color has-alpha-channel-opacity has-pale-cyan-blue-background-color has-background\"\/>\n<p><strong>Abstract<\/strong><\/p>\n<p><strong>Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that precede neurological dysfunction and inform pathogenic cascade<\/strong><\/p>\n<p>Mutations in the X-linked methyl-CpG-binding protein 2 (<em>MECP2<\/em>) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions.<\/p>\n<p> To understand what drives such dysregulation, we deleted\u00a0<em>Mecp2<\/em>\u00a0in adult mice, circumventing developmental contributions and secondary pathogenesis.<\/p>\n<p>We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome.<\/p>\n<p>To understand what drives gene downregulation, we profiled genome-wide histone modifications and found that a decrease in histone H3 acetylation (ac) at downregulated genes is among the earliest molecular changes occurring well before any measurable deficiencies in electrophysiology and neurological function.<\/p>\n<p>These data reveal a molecular cascade that drives disease independent of any developmental contributions or secondary pathogenesis.<\/p>\n<p> <!-- Form created by Optin Forms plugin by WPKube: create beautiful optin forms with ease! --> <!-- https:\/\/wpkube.com\/ --><!--optinforms-form5-container--> <!-- \/ Optin Forms --> <\/div>\n<p><script async src=\"https:\/\/pagead2.googlesyndication.com\/pagead\/js\/adsbygoogle.js?client=ca-pub-3711241968723425\"\r\n     crossorigin=\"anonymous\"><\/script>\r\n<ins class=\"adsbygoogle\"\r\n     style=\"display:block\"\r\n     data-ad-format=\"fluid\"\r\n     data-ad-layout-key=\"-fb+5w+4e-db+86\"\r\n     data-ad-client=\"ca-pub-3711241968723425\"\r\n     data-ad-slot=\"7910942971\"><\/ins>\r\n<script>\r\n     (adsbygoogle = window.adsbygoogle || []).push({});\r\n<\/script><br \/>\n<br \/><div data-type=\"_mgwidget\" data-widget-id=\"1660802\">\r\n<\/div>\r\n<script>(function(w,q){w[q]=w[q]||[];w[q].push([\"_mgc.load\"])})(window,\"_mgq\");\r\n<\/script>\r\n<br \/>\n<br \/><a href=\"https:\/\/neurosciencenews.com\/mecp2-genetics-rett-syndrome-28256\/\">Source link <\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Summary: Researchers have uncovered how loss of the MeCP2 protein triggers early molecular changes leading to Rett syndrome, a severe neurological disorder. By studying adult mice, they demonstrated that MeCP2 &hellip; <a href=\"https:\/\/hotvideos24.online\/?p=137918\" class=\"more-link\">Read More<\/a><\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7],"tags":[],"class_list":["post-137918","post","type-post","status-publish","format-standard","hentry","category-health","entry"],"_links":{"self":[{"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/posts\/137918","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=137918"}],"version-history":[{"count":0,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/posts\/137918\/revisions"}],"wp:attachment":[{"href":"https:\/\/hotvideos24.online\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=137918"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=137918"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=137918"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}