{"id":6271,"date":"2020-11-24T16:49:34","date_gmt":"2020-11-24T07:49:34","guid":{"rendered":"http:\/\/www.med.osaka-u.ac.jp\/eng\/?page_id=6271"},"modified":"2022-08-26T14:48:22","modified_gmt":"2022-08-26T05:48:22","slug":"nagano2020","status":"publish","type":"page","link":"https:\/\/www.med.osaka-u.ac.jp\/eng\/activities\/results\/2020year\/nagano2020","title":{"rendered":"Seiichi Nagano,  Hideki Mochizuki\u226aNeurology\u226b <span>Faulty transportation of messenger RNA is the culprit in ALS<\/span>"},"content":{"rendered":"<ul class=\"linkBar clearfix\">\n<li><a href=\"http:\/\/www.med.osaka-u.ac.jp\/activities\/results\/2020year\/nagano202009\">Text in Japanese<\/a><\/li>\n<\/ul>\n<p><strong><em><\/p>\n<p><span class=\"lineFrame\">Publish\u00a0<\/span> <em>Acta Neuropathologica <\/em><br \/><\/strong><\/p>\n<p><em>The lack of protein TDP-43 in two neurodegenerative diseases is shown to prevent neuron growth via failed transport of RNA and subsequent absence of protein synthesis in axons<\/em><strong>\u00a0<\/strong><\/p>\n<p class=\"figure\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-6277 size-medium\" src=\"http:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2020\/11\/4c91d76fc4075d5b09d799ccb1e3fc4d-400x247.jpg?_t=1606355487\" alt=\"\" width=\"400\" height=\"247\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2020\/11\/4c91d76fc4075d5b09d799ccb1e3fc4d-400x247.jpg 400w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2020\/11\/4c91d76fc4075d5b09d799ccb1e3fc4d.jpg 584w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><a href=\"http:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2020\/11\/4c91d76fc4075d5b09d799ccb1e3fc4d.jpg\"> <span class=\"caption\"><strong>Fig.1 Ribosomal protein mRNA partially reversed impaired axonal outgrowth found in TDP-43-knockdown neurons. <br \/><\/strong>Decrease of TDP-43 in mouse cortical neurons impaired axonal outgrowth, which was significantly improved by overexpression of individual ribosomal protein mRNAs\u00a0\u00a0<strong><strong><\/p>\n<p><span class=\"click\">Click to enlarge<\/span><\/strong><\/strong><\/span><\/a><\/p>\n<p>As the current COVID-19 crisis has shown, the disruptions that occur when transportation cannot proceed as usual are system-wide, affecting individual lives, companies, and the global economy. Now imagine a similar problem inside your brain and spinal cord. A new study led by researchers from Osaka University and National Center of Neurology and Psychiatry reports that two common neurodegenerative diseases\u2014ALS, also known as Lou Gehrig&#8217;s disease, and frontotemporal lobar degeneration, or FTLD\u2014result from reduced transportation of RNA by the protein TDP-43, which ultimately disrupts neuron function.<\/p>\n<p>Because one of the biggest physiological changes in both ALS and FTLD is the disappearance of TDP-43 from the nucleoli of neurons, the team focused their research on finding out what TDP-43 normally does. TDP-43 is known to bind to RNA, and the team\u2019s first experiment showed that in neurons, TDP-43 attaches to RNA that codes for pieces of ribosomes, which are necessary for making proteins from RNA code.<\/p>\n<p>At its core, transportation gets things where they need to be at the proper time, whether they\u2019re people, goods, or molecules. In the body, items being sent from one place to another are often a response to what\u2019s happening to you. For instance, in response to dehydration, your brain sends a hormone through your blood to the kidneys where it forces water to be reabsorbed. In cells like neurons, the situation is similar, but there are no roads or arteries. Instead, many molecules get to their destination by being carried by other molecules.<\/p>\n<p>\u201cWe discovered TDP-43 in axons and that it binds to ribosomal protein messenger RNA,\u201d says first author Seiichi Nagano. \u201cThat was strong support for the idea that TDP-43 carries the RNA to the axon where it can be used to make ribosomal proteins. This would allow local synthesis of proteins at ribosomes built in axons.\u201d Indeed, further experiments confirmed that hypothesis and showed that when TDP-43 was missing, the RNA in question could not be transported to the axon.<\/p>\n<p>But what happens if the RNA cannot be transported? The researchers examined axon growth in culture as well as in mouse embryos. They found that in both cases, axon extension and outgrowth were stunted when TDP-43 was missing. However, outgrowth could be restored by forcing the neurons to overproduce ribosomal proteins.<\/p>\n<p>\u201cNow that we understand TDP-43\u2019s role in transporting the ribosomal protein messenger RNA, it should help us develop new strategies and new targets for ALS and FTLD treatments,\u201d says co-author of the study Hideki Mochizuki. \u201cOur results in reversing stunted axon extension in mouse embryos is promising, but is just a first step.\u201d<\/p>\n<p>The article, \u201cTDP\u201043 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons,\u201d was published in <em>Acta Neuropathologica <\/em>at DOI: <a href=\"https:\/\/doi.org\/10.1007\/s00401-020-02205-y\">https:\/\/doi.org\/10.1007\/s00401-020-02205-y<\/a><\/p>\n<p><strong>Summary:<\/strong><\/p>\n<p>A team including Osaka University researchers has discovered a function for the protein missing in many types of ALS and FTLD, two neurodegenerative diseases. In neurons, the protein TDP-43 bound to messenger RNA that codes for pieces of ribosomes, the structures where proteins are made. Further tests showed that this allowed the RNA to be transported down to the axons, where it could promote axon growth and extension.<\/p>\n<p><strong>Primary keyword: <\/strong>Biology<\/p>\n<p><strong>Secondary keywords<\/strong>: Molecular biology, Cell Biology, Neurobiology, Medicine\/Health,<\/p>\n<p><strong>\u00a0<\/strong><\/p>\n<p><strong>\u00a0<\/strong><\/p>\n<p class=\"figure\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-6279 size-medium\" src=\"http:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2020\/11\/68590025916832e9ed37ab10a59287a7-400x226.jpg?_t=1606355503\" alt=\"\" width=\"400\" height=\"226\" srcset=\"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2020\/11\/68590025916832e9ed37ab10a59287a7-400x226.jpg 400w, https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2020\/11\/68590025916832e9ed37ab10a59287a7.jpg 593w\" sizes=\"(max-width: 400px) 100vw, 400px\" \/><a href=\"http:\/\/www.med.osaka-u.ac.jp\/eng\/wp-content\/uploads\/2020\/11\/68590025916832e9ed37ab10a59287a7.jpg\"> <span class=\"caption\"><strong>Fig. 2 Model of ALS\/FTLD pathology associated with abnormal deposition of TDP-43<br \/><strong><br \/><span class=\"click\">Click to enlarge<\/span><\/strong><\/strong><\/span><\/a><\/p>\n<p>Title: \u201cTDP\u201143 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons\u201d<br \/>Journal: <em>Acta Neuropathologica<br \/><\/em><\/p>\n<p>Authors: Seiichi Nagano, Junki Jinno, Rehab F. Abdelhamid, Yinshi Jin, Megumi Shibata, Shohei Watanabe, Sachiko Hirokawa, Masatoyo Nishizawa, Kenji Sakimura, Osamu Onodera, Hironori Okada, Takashi Okada, Yuko Saito, Junko Takahashi\u2011Fujigasaki, Shigeo Murayama, Shuji Wakatsuki, Hideki Mochizuki, Toshiyuki Araki<\/p>\n<p>DOI: 10.1007\/s00401-020-02205-y<br \/>Funded by: Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development<\/p>\n<p>&nbsp;<\/p>\n<p><strong>About Osaka University <\/strong><\/p>\n<p>Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan&#8217;s leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan&#8217;s most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.<\/p>\n<p>Website: <a href=\"https:\/\/resou.osaka-u.ac.jp\/en\/top\">https:\/\/resou.osaka-u.ac.jp\/en\/top<\/a><\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Text in Japanese Publish\u00a0 Acta Neuropathologica The lack of protein TDP-43 in two neurodegenerative diseases i [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":6279,"parent":5550,"menu_order":64,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"_links":{"self":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/6271"}],"collection":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/comments?post=6271"}],"version-history":[{"count":16,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/6271\/revisions"}],"predecessor-version":[{"id":7588,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/6271\/revisions\/7588"}],"up":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/pages\/5550"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/media\/6279"}],"wp:attachment":[{"href":"https:\/\/www.med.osaka-u.ac.jp\/eng\/wp-json\/wp\/v2\/media?parent=6271"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}