{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:10:05Z","timestamp":1779084605083,"version":"3.51.4"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2013,9,24]],"date-time":"2013-09-24T00:00:00Z","timestamp":1379980800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"},{"start":{"date-parts":[[2013,9,24]],"date-time":"2013-09-24T00:00:00Z","timestamp":1379980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["EMBO Mol Med"],"published-print":{"date-parts":[[2013,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Amyotrophic lateral sclerosis (ALS) is the most common adult\u2010onset motor neuron disease, and the lack of effective therapy results in inevitable death within a few years of onset. Failure of GluA2 RNA editing resulting from downregulation of the RNA\u2010editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) occurs in the majority of ALS cases and causes the death of motor neurons via a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010permeable AMPA receptor\u2010mediated mechanism. Here, we explored the possibility of gene therapy for ALS by upregulating ADAR2 in mouse motor neurons using an adeno\u2010associated virus serotype 9 (AAV9) vector that provides gene delivery to a wide array of central neurons after peripheral administration. A single intravenous injection of AAV9\u2010ADAR2 in conditional ADAR2 knockout mice (AR2), which comprise a mechanistic mouse model of sporadic ALS, caused expression of exogenous ADAR2 in the central neurons and effectively prevented progressive motor dysfunction. Notably, AAV9\u2010ADAR2 rescued the motor neurons of AR2 mice from death by normalizing TDP\u201043 expression. This AAV9\u2010mediated ADAR2 gene delivery may therefore enable the development of a gene therapy for ALS.\n                  <\/jats:p>","DOI":"10.1002\/emmm.201302935","type":"journal-article","created":{"date-parts":[[2013,10,11]],"date-time":"2013-10-11T21:00:01Z","timestamp":1381525201000},"page":"1710-1719","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9\u2010ADAR2 delivery to motor neurons"],"prefix":"10.1038","volume":"5","author":[{"given":"Takenari","family":"Yamashita","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui Lin","family":"Chai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayaka","family":"Teramoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoji","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuniko","family":"Shimazaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin\u2010ichi","family":"Muramatsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin","family":"Kwak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2013,9,24]]},"reference":[{"key":"BFEMMM201302935_CR1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s00401-010-0678-x","volume":"120","author":"H Aizawa","year":"2010","unstructured":"Aizawa H, Sawada J, Hideyama T, Yamashita T, Katayama T, Hasebe N, Kimura T, Yahara O, Kwak S (2010) TDP\u201043 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. Acta Neuropathol 120: 75-84","journal-title":"Acta Neuropathol"},{"key":"BFEMMM201302935_CR2","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","volume":"351","author":"T Arai","year":"2006","unstructured":"Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y et al (2006) TDP\u201043 is a component of ubiquitin\u2010positive tau\u2010negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351: 602-611","journal-title":"Biochem Biophys Res Commun"},{"key":"BFEMMM201302935_CR3","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/mt.2012.261","volume":"21","author":"S Benkhelifa\u2010Ziyyat","year":"2013","unstructured":"Benkhelifa\u2010Ziyyat S, Besse A, Roda M, Duque S, Astord S, Carcenac R, Marais T, Barkats M (2013) Intramuscular scAAV9\u2010SMN injection mediates widespread gene delivery to the spinal cord and decreases disease severity in SMA mice. Mol Ther 21: 282-290","journal-title":"Mol Ther"},{"key":"BFEMMM201302935_CR4","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1038\/nsmb825","volume":"11","author":"T Bhalla","year":"2004","unstructured":"Bhalla T, Rosenthal JJ, Holmgren M, Reenan R (2004) Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nat Struct Mol Biol 11: 950-956","journal-title":"Nat Struct Mol Biol"},{"key":"BFEMMM201302935_CR5","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1517\/14712598.2012.681463","volume":"12","author":"RD Dayton","year":"2012","unstructured":"Dayton RD, Wang DB, Klein RL (2012) The advent of AAV9 expands applications for brain and spinal cord gene delivery. Expert Opin Biol Ther 12: 757-766","journal-title":"Expert Opin Biol Ther"},{"key":"BFEMMM201302935_CR6","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1038\/mt.2009.71","volume":"17","author":"S Duque","year":"2009","unstructured":"Duque S, Joussemet B, Riviere C, Marais T, Dubreil L, Douar AM, Fyfe J, Moullier P, Colle MA, Barkats M (2009) Intravenous administration of self\u2010complementary AAV9 enables transgene delivery to adult motor neurons. Mol Ther 17: 1187-1196","journal-title":"Mol Ther"},{"key":"BFEMMM201302935_CR7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nbt.1515","volume":"27","author":"KD Foust","year":"2009","unstructured":"Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK (2009) Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 27: 59-65","journal-title":"Nat Biotechnol"},{"key":"BFEMMM201302935_CR8","doi-asserted-by":"crossref","first-page":"6381","DOI":"10.1128\/JVI.78.12.6381-6388.2004","volume":"78","author":"G Gao","year":"2004","unstructured":"Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, Wilson JM (2004) Clades of adeno\u2010associated viruses are widely disseminated in human tissues. J Virol 78: 6381-6388","journal-title":"J Virol"},{"key":"BFEMMM201302935_CR9","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3389\/fnmol.2011.00033","volume":"4","author":"T Hideyama","year":"2011","unstructured":"Hideyama T, Kwak S (2011) When does ALS start? ADAR2\u2010GluA2 hypothesis for the etiology of sporadic ALS. Front Mol Neurosci 4: 33","journal-title":"Front Mol Neurosci"},{"key":"BFEMMM201302935_CR10","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.nbd.2011.12.033","volume":"45","author":"T Hideyama","year":"2012","unstructured":"Hideyama T, Yamashita T, Aizawa H, Tsuji S, Kakita A, Takahashi H, Kwak S (2012) Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons. Neurobiol Dis 45: 1121-1128","journal-title":"Neurobiol Dis"},{"key":"BFEMMM201302935_CR11","doi-asserted-by":"crossref","first-page":"11917","DOI":"10.1523\/JNEUROSCI.2021-10.2010","volume":"30","author":"T Hideyama","year":"2010","unstructured":"Hideyama T, Yamashita T, Suzuki T, Tsuji S, Higuchi M, Seeburg PH, Takahashi R, Misawa H, Kwak S (2010) Induced loss of ADAR2 engenders slow death of motor neurons from Q\/R site\u2010unedited GluR2. J Neurosci 30: 11917-11925","journal-title":"J Neurosci"},{"key":"BFEMMM201302935_CR12","first-page":"134ra161","volume":"4","author":"WL Hwu","year":"2012","unstructured":"Hwu WL, Muramatsu S, Tseng SH, Tzen KY, Lee NC, Chien YH, Snyder RO, Byrne BJ, Tai CH, Wu RM (2012) Gene therapy for aromatic l\u2010amino acid decarboxylase deficiency. Sci Transl Med 4: 134ra161","journal-title":"Sci Transl Med"},{"key":"BFEMMM201302935_CR13","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1038\/srep01472","volume":"3","author":"N Iwata","year":"2013","unstructured":"Iwata N, Sekiguchi M, Hattori Y, Takahashi A, Asai M, Ji B, Higuchi M, Staufenbiel M, Muramatsu S, Saido TC (2013) Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice. Sci Rep 3: 1472","journal-title":"Sci Rep"},{"key":"BFEMMM201302935_CR14","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/427801a","volume":"427","author":"Y Kawahara","year":"2004","unstructured":"Kawahara Y, Ito K, Sun H, Aizawa H, Kanazawa I, Kwak S (2004) Glutamate receptors: RNA editing and death of motor neurons. Nature 427: 801","journal-title":"Nature"},{"key":"BFEMMM201302935_CR15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1046\/j.1460-9568.2003.02718.x","volume":"18","author":"Y Kawahara","year":"2003","unstructured":"Kawahara Y, Ito K, Sun H, Kanazawa I, Kwak S (2003) Low editing efficiency of GluR2 mRNA is associated with a low relative abundance of ADAR2 mRNA in white matter of normal human brain. Eur J Neurosci 18: 23-33","journal-title":"Eur J Neurosci"},{"key":"BFEMMM201302935_CR16","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s00109-004-0599-z","volume":"83","author":"S Kwak","year":"2005","unstructured":"Kwak S, Kawahara Y (2005) Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. J Mol Med 83: 110-120","journal-title":"J Mol Med"},{"key":"BFEMMM201302935_CR17","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ymthe.2005.08.009","volume":"13","author":"XG Li","year":"2006","unstructured":"Li XG, Okada T, Kodera M, Nara Y, Takino N, Muramatsu C, Ikeguchi K, Urano F, Ichinose H, Metzger D et al (2006) Viral\u2010mediated temporally controlled dopamine production in a rat model of Parkinson disease. Mol Ther 13: 160-166","journal-title":"Mol Ther"},{"key":"BFEMMM201302935_CR18","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1152\/physiolgenomics.00120.2004","volume":"20","author":"T Lonergan","year":"2005","unstructured":"Lonergan T, Teschemacher AG, Hwang DY, Kim KS, Pickering AE, Kasparov S (2005) Targeting brain stem centers of cardiovascular control using adenoviral vectors: impact of promoters on transgene expression. Physiol Genomics 20: 165-172","journal-title":"Physiol Genomics"},{"key":"BFEMMM201302935_CR19","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nrg2988","volume":"12","author":"F Mingozzi","year":"2011","unstructured":"Mingozzi F, High KA (2011) Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet 12: 341-355","journal-title":"Nat Rev Genet"},{"key":"BFEMMM201302935_CR20","doi-asserted-by":"crossref","first-page":"e2050","DOI":"10.1371\/journal.pone.0002050","volume":"3","author":"T Nakamura","year":"2008","unstructured":"Nakamura T, Takumi T, Takano A, Aoyagi N, Yoshiuchi K, Struzik ZR, Yamamoto Y (2008) Of mice and men\u2014universality and breakdown of behavioral organization. PLoS ONE 3: e2050","journal-title":"PLoS ONE"},{"key":"BFEMMM201302935_CR21","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1126\/science.1134108","volume":"314","author":"M Neumann","year":"2006","unstructured":"Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM et al (2006) Ubiquitinated TDP\u201043 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130-133","journal-title":"Science"},{"key":"BFEMMM201302935_CR22","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.neures.2008.02.009","volume":"61","author":"Y Nishimoto","year":"2008","unstructured":"Nishimoto Y, Yamashita T, Hideyama T, Tsuji S, Suzuki N, Kwak S (2008) Determination of editors at the novel A\u2010to\u2010I editing positions. Neurosci Res 61: 201-206","journal-title":"Neurosci Res"},{"key":"BFEMMM201302935_CR23","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/mt.2010.234","volume":"19","author":"H Petrs\u2010Silva","year":"2011","unstructured":"Petrs\u2010Silva H, Dinculescu A, Li Q, Deng WT, Pang JJ, Min SH, Chiodo V, Neeley AW, Govindasamy L, Bennett A et al (2011) Novel properties of tyrosine\u2010mutant AAV2 vectors in the mouse retina. Mol Ther 19: 293-301","journal-title":"Mol Ther"},{"key":"BFEMMM201302935_CR24","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.neures.2009.03.009","volume":"64","author":"J Sawada","year":"2009","unstructured":"Sawada J, Yamashita T, Aizawa H, Aburakawa Y, Hasebe N, Kwak S (2009) Effects of antidepressants on GluR2 Q\/R site\u2010RNA editing in modified HeLa cell line. Neurosci Res 64: 251-258","journal-title":"Neurosci Res"},{"key":"BFEMMM201302935_CR25","doi-asserted-by":"crossref","first-page":"22448","DOI":"10.1074\/jbc.M700265200","volume":"282","author":"M Singh","year":"2007","unstructured":"Singh M, Kesterson RA, Jacobs MM, Joers JM, Gore JC, Emeson RB (2007) Hyperphagia\u2010mediated obesity in transgenic mice misexpressing the RNA\u2010editing enzyme ADAR2. J Biol Chem 282: 22448-22459","journal-title":"J Biol Chem"},{"key":"BFEMMM201302935_CR26","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1089\/hum.2012.013","volume":"23","author":"E Thevenot","year":"2012","unstructured":"Thevenot E, Jordao JF, O'Reilly MA, Markham K, Weng YQ, Foust KD, Kaspar BK, Hynynen K, Aubert I (2012) Targeted delivery of self\u2010complementary adeno\u2010associated virus serotype 9 to the brain, using magnetic resonance imaging\u2010guided focused ultrasound. Hum Gene Ther 23: 1144-1155","journal-title":"Hum Gene Ther"},{"key":"BFEMMM201302935_CR27","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1038\/ncomms2303","volume":"3","author":"T Yamashita","year":"2012","unstructured":"Yamashita T, Hideyama T, Hachiga K, Teramoto S, Takano J, Iwata N, Saido TC, Kwak S (2012a) A role for calpain\u2010dependent cleavage of TDP\u201043 in amyotrophic lateral sclerosis pathology. Nat Commun 3: 1307","journal-title":"Nat Commun"},{"key":"BFEMMM201302935_CR28","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.neures.2012.02.015","volume":"73","author":"T Yamashita","year":"2012","unstructured":"Yamashita T, Hideyama T, Teramoto S, Kwak S (2012b) The abnormal processing of TDP\u201043 is not an upstream event of reduced ADAR2 activity in ALS motor neurons. Neurosci Res 73: 153-160","journal-title":"Neurosci Res"},{"key":"BFEMMM201302935_CR29","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.neures.2012.02.002","volume":"73","author":"T Yamashita","year":"2012","unstructured":"Yamashita T, Tadami C, Nishimoto Y, Hideyama T, Kimura D, Suzuki T, Kwak S (2012c) RNA editing of the Q\/R site of GluA2 in different cultured cell lines that constitutively express different levels of RNA editing enzyme ADAR2. Neurosci Res 73: 42-48","journal-title":"Neurosci Res"}],"container-title":["EMBO Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1002\/emmm.201302935.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/emmm.201302935","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1002\/emmm.201302935\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.embopress.org\/doi\/pdf\/10.1002\/emmm.201302935","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1002\/emmm.201302935.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:05:47Z","timestamp":1779084347000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1002\/emmm.201302935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9,24]]},"references-count":29,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2013,11,1]]}},"alternative-id":["BFEMMM201302935"],"URL":"https:\/\/doi.org\/10.1002\/emmm.201302935","relation":{},"ISSN":["1757-4676","1757-4684"],"issn-type":[{"value":"1757-4676","type":"print"},{"value":"1757-4684","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,9,24]]},"assertion":[{"value":"22 April 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 August 2013","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 August 2013","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 September 2013","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}]}}