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Patients with NPC disease have markedly progressive neuronal loss, mainly of cerebellar Purkinje neurons. There is strong evidence indicating that cholesterol accumulation and trafficking defects activate apoptosis in NPC brains. The purpose of this study was to analyze the relevance of apoptosis and particularly the proapoptotic c\u2010Abl\/ p73 system in cerebellar neuron degeneration in NPC disease. We used the NPC1 mouse model to evaluate c\u2010Abl\/p73 expression and activation in the cerebellum and the effect of therapy with the c\u2010Abl\u2010specific inhibitor imatinib. The proapoptotic c\u2010Abl\/p73 system and the p73 target genes are expressed in the cerebellums of NPC mice. Furthermore, inhibition of c\u2010Abl with imatinib preserved Purkinje neurons and reduced general cell apoptosis in the cerebellum, improved neurological symptoms, and increased the survival of NPC mice. Moreover, this prosurvival effect correlated with reduced mRNA levels of p73 proapoptotic target genes. Our results suggest that the c\u2010Abl\/p73 pathway is involved in NPC neurodegeneration and show that treatment with c\u2010Abl inhibitors is useful in delaying progressive neurodegeneration, supporting the use of imatinib for clinical treatment of patients with NPC disease.\u2014Alvarez, A. R., Klein, A., Castro, J., Cancino, G. I., Amigo, J., Mosqueira, M., Vargas, L. M., Y\u00e9venes, L. F., Bronfman, F. C., Zanlungo, S. Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann Pick type C disease.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    22, 3617\u20133627 (2008)\n                  <\/jats:p>","DOI":"10.1096\/fj.07-102715","type":"journal-article","created":{"date-parts":[[2008,6,30]],"date-time":"2008-06-30T20:44:57Z","timestamp":1214858697000},"page":"3617-3627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann\u2010Pick type C disease"],"prefix":"10.1096","volume":"22","author":[{"given":"Alejandra R.","family":"Alvarez","sequence":"first","affiliation":[{"name":"Departamento de Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Klein","sequence":"additional","affiliation":[{"name":"Departamento de Gastroenterolog\u00eda, Facultad de Medicina Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Castro","sequence":"additional","affiliation":[{"name":"Departamento de Gastroenterolog\u00eda, Facultad de Medicina Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo I.","family":"Cancino","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Amigo","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mat\u00edas","family":"Mosqueira","sequence":"additional","affiliation":[{"name":"Departamento de Gastroenterolog\u00eda, Facultad de Medicina Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina M.","family":"Vargas","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Fernanda","family":"Yevenes","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Celular y Molecular, Facultad de Ciencias Biol\u00f3gicas Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca C.","family":"Bronfman","sequence":"additional","affiliation":[{"name":"Centro de Regulaci\u00f3n Celular y Patolog\u00eda, Joaqu\u00edn V. Luco (CRCP), Departamento de Ciencias Fisiol\u00f3gicas, Facultad de Ciencias Biol\u00f3gicas Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvana","family":"Zanlungo","sequence":"additional","affiliation":[{"name":"Departamento de Gastroenterolog\u00eda, Facultad de Medicina Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,6,30]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2004.08.008"},{"key":"e_1_2_6_3_1","first-page":"2625","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Pentchev P.G.","year":"1995"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-199804000-00009"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0004.2003.00147.x"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31735"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.21200"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.nrl.0000094627.78754.5b"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.162.5.1021-a"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1176\/jnp.2006.18.2.158"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.209.263"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-198805000-00008"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2004.08.011"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2004.08.017"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/64.4.323"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05293"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1732494100"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.08.029"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R400008200"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000019"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/1073858404263456"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207342"},{"key":"e_1_2_6_23_1","first-page":"3418","article-title":"c\u2010Abl stabilizes p73 by a phosphorylation\u2010augmented interaction","volume":"63","author":"Tsai K. 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