Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease

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dc.contributor.authorAlvarez, Alejandra R.
dc.contributor.authorKlein, Andres
dc.contributor.authorCastro, Juan
dc.contributor.authorCancino, Gonzalo I.
dc.contributor.authorAmigo, Julio
dc.contributor.authorMosqueira, Matias
dc.contributor.authorVargas, Lina M.
dc.contributor.authorYevenes, L. Fernanda
dc.contributor.authorBronfman, Francisca C.
dc.contributor.authorZanlungo, Silvana
dc.date.accessioned2024-01-10T13:49:15Z
dc.date.available2024-01-10T13:49:15Z
dc.date.issued2008
dc.description.abstractNiemann-Pick type C (NPC) disease is a fatal autosomal recessive disorder characterized by the accumulation of free cholesterol and glycosphingo-lipids in the endosomal-lysosomal system. 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-Abl/p73 system in cerebellar neuron degeneration in NPC disease. We used the NPC1 mouse model to evaluate c-Abl/p73 expression and activation in the cerebellum and the effect of therapy with the c-Abl-specific inhibitor imatinib. The proapoptotic c-Abl/p73 system and the p73 target genes are expressed in the cerebellums of NPC mice. Furthermore, inhibition of c-Abl 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-Abl/p73 pathway is involved in NPC neurodegeneration and show that treatment with c-Abl inhibitors is useful in delaying progressive neurodegeneration, supporting the use of imatinib for clinical treatment of patients with NPC disease.
dc.description.funderAra Parseghian Medical Research Foundation
dc.description.funderFondo Nacional de Desarrollo Cientifico y Tecnologico
dc.fechaingreso.objetodigital2024-05-02
dc.format.extent11 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1096/fj.07-102715
dc.identifier.eissn1530-6860
dc.identifier.issn0892-6638
dc.identifier.pubmedidMEDLINE:18591368
dc.identifier.urihttps://doi.org/10.1096/fj.07-102715
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/79435
dc.identifier.wosidWOS:000259642600023
dc.information.autorucCiencias Biológicas;Bronfman F;S/I;86829
dc.information.autorucCiencias Biológicas;Cancino G;S/I;17709
dc.information.autorucMedicina;Castro J;S/I;8518
dc.information.autorucCiencias Biológicas;Klein A;S/I;2966
dc.information.autorucCiencias Biológicas;Mosqueira M;S/I;1231
dc.information.autorucCiencias Biológicas;Vargas L;S/I;174079
dc.information.autorucCiencias Biológicas;Yévenes L;S/I;142390
dc.information.autorucMedicina;Zanlungo S;S/I;72650
dc.information.autorucCiencias Biológicas;Álvarez A;S/I;83681
dc.issue.numero10
dc.language.isoen
dc.nota.accesocontenido parcial
dc.pagina.final3627
dc.pagina.inicio3617
dc.publisherWILEY
dc.revistaFASEB JOURNAL
dc.rightsacceso restringido
dc.subjectneurodegeneration
dc.subjectc-Abl/p73
dc.subjectcholesterol
dc.subjectABL TYROSINE KINASE
dc.subjectAMYOTROPHIC-LATERAL-SCLEROSIS
dc.subjectUNFOLDED PROTEIN RESPONSE
dc.subjectCELL-DEATH
dc.subjectNEURONAL DEATH
dc.subjectENDOPLASMIC-RETICULUM
dc.subjectCEREBROSPINAL-FLUID
dc.subjectANTICANCER DRUG
dc.subjectP73
dc.subjectMICE
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleImatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease
dc.typeartículo
dc.volumen22
sipa.codpersvinculados86829
sipa.codpersvinculados17709
sipa.codpersvinculados8518
sipa.codpersvinculados2966
sipa.codpersvinculados1231
sipa.codpersvinculados174079
sipa.codpersvinculados142390
sipa.codpersvinculados72650
sipa.codpersvinculados83681
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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