title: Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease.
abstract: Niemann-Pick type C (NPC) disease is a fatal autosomal recessive disorder characterized by the accumulation of free cholesterol and glycosphingolipids 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.
authors.affiliation: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, casilla 114-D, Santiago, Chile. aalvarez@bio.puc.cl
authors.forename: Alejandra R
authors.initials: AR
authors.lastname: Alvarez
authors.forename: Andrés
authors.initials: A
authors.lastname: Klein
authors.forename: Juan
authors.initials: J
authors.lastname: Castro
authors.forename: Gonzalo I
authors.initials: GI
authors.lastname: Cancino
authors.forename: Julio
authors.initials: J
authors.lastname: Amigo
authors.forename: Matías
authors.initials: M
authors.lastname: Mosqueira
authors.forename: Lina M
authors.initials: LM
authors.lastname: Vargas
authors.forename: L Fernanda
authors.initials: LF
authors.lastname: Yévenes
authors.forename: Francisca C
authors.initials: FC
authors.lastname: Bronfman
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002470:Cell Survival / Q000187:drug effects; D002525:Cerebellar Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011506:Proteins / Q000235:genetics; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects / Q000473:pathology; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D001549:Benzamides; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D009687:Nuclear Proteins; D010879:Piperazines; D011506:Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl