{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T09:14:49Z","timestamp":1761988489038},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2012,7,1]],"date-time":"2012-07-01T00:00:00Z","timestamp":1341100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Ataxia-telangiectasia (A-T) is a progressive degenerative disorder that results in major neurological disability. In A-T patients, necropsy has revealed atrophy of cerebellar cortical layers along with Purkinje and granular cell loss. We have previously identified an oxidative stress-mediated increase in phospho-p38 mitogen-activated protein kinase (MAPK) and the resultant downregulation of Bmi-1 and upregulation of p21 as key components of the mechanism causing defective proliferation of neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of Atm\u2212\/\u2212 mice. However, the in vivo aspect of alteration in SVZ tissue and the functional significance of p38MAPK activation in NSCs for neuropathogenesis of ATM deficiency remain unknown. Here we show that the NSC population was abnormally decreased in the SVZ of 3-month-old Atm\u2212\/\u2212 mice; this decrease was accompanied by p38MAPK activation. However, after a 2-month treatment with the p38MAPK inhibitor SB203580, starting at 1 month old, Atm\u2212\/\u2212 mice showed restoration of normal levels of Bmi-1 and p21 with the rescue of NSC population in the SVZ. In addition, treated Atm\u2212\/\u2212 mice exhibited more Purkinje cells in the cerebellum. Most importantly, motor coordination of Atm\u2212\/\u2212 mice was significantly improved in the treatment group. Our results show for the first time in vivo evidence of depleted NSCs in the SVZ of Atm\u2212\/\u2212 mice and also demonstrate that pharmacologic inhibition of p38MAPK signaling has the potential to treat neurological defects of A-T. This study provides a promising approach targeting the oxidative stress-dependent p38 signaling pathway not only for A-T but also for other neurodegenerative disorders.<\/jats:p>","DOI":"10.5966\/sctm.2011-0063","type":"journal-article","created":{"date-parts":[[2012,7,7]],"date-time":"2012-07-07T04:37:36Z","timestamp":1341635856000},"page":"548-556","source":"Crossref","is-referenced-by-count":9,"title":["Targeting p38 Mitogen-Activated Protein Kinase Signaling Restores Subventricular Zone Neural Stem Cells and Corrects Neuromotor Deficits in <i>Atm<\/i> Knockout Mouse"],"prefix":"10.1093","volume":"1","author":[{"given":"Jeesun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul K.Y.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2012,7,6]]},"reference":[{"key":"2021122705463956900_ref1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/00005792-199103000-00003","article-title":"Ataxia-telangiectasia: An interdisciplinary approach to pathogenesis","volume":"70","author":"Gatti","year":"1991","journal-title":"Medicine (Baltimore)"},{"key":"2021122705463956900_ref2","first-page":"1","volume-title":"Neurodegeneration: Theory, Disorders and Treatments","author":"Wong","year":"2010"},{"key":"2021122705463956900_ref3","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/ana.410130312","article-title":"Cerebellar cortex ultrastructure in ataxia-telangiectasia","volume":"13","author":"Paula-Barbosa","year":"1983","journal-title":"Ann 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