title: Neuronal gene repression in Niemann-Pick type C models is mediated by the c-Abl/HDAC2 signaling pathway.
abstract: BACKGROUND
  Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. There are currently no effective FDA-approved treatments for NPC, although in the last years the inhibition of histone deacetylases (HDACs) has emerged as a potential treatment for this disease. However, the molecular mechanisms that deregulate HDAC activity in NPC disease are unknown. Previously our group had shown that the proapoptotic tyrosine kinase c-Abl signaling is activated in NPC neurons. Here, we demonstrate that c-Abl activity increases HDAC2 levels inducing neuronal gene repression of key synaptic genes in NPC models.
  
  
  RESULTS
  Our data show that: i) HDAC2 levels and activity are increased in NPC neuronal models and in Npc1(-/-) mice; ii) inhibition of c-Abl or c-Abl deficiency prevents the increase of HDAC2 protein levels and activity in NPC neuronal models; iii) c-Abl inhibition decreases the levels of HDAC2 tyrosine phosphorylation; iv) treatment with methyl-β-cyclodextrin and vitamin E decreases the activation of the c-Abl/HDAC2 pathway in NPC neurons; v) in vivo treatment with two c-Abl inhibitors prevents the increase of HDAC2 protein levels in the brain of Npc1(-/-) mice; and vi) c-Abl inhibition prevents HDAC2 recruitment to the promoter of neuronal genes, triggering an increase in their expression.
  
  
  CONCLUSIONS
  Our data show the involvement of the c-Abl/HDAC2 signaling pathway in the regulation of neuronal gene expression in NPC neuronal models. Thus, inhibition of c-Abl could be a pharmacological target for preventing the deleterious effects of increased HDAC2 levels in NPC disease.
authors.affiliation: Department of Cell and Molecular Biology, Pontificia Universidad Católica de Chile, Santiago, Chile; CARE UC Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Pablo S
authors.initials: PS
authors.lastname: Contreras
authors.affiliation: Department of Cell and Molecular Biology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Gonzalez-Zuñiga
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Lila
authors.initials: L
authors.lastname: González-Hódar
authors.affiliation: Department of Cell and Molecular Biology, Pontificia Universidad Católica de Chile, Santiago, Chile; CARE UC Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: María José
authors.initials: MJ
authors.lastname: Yáñez
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Andrés
authors.initials: A
authors.lastname: Dulcey
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Marugan
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.affiliation: Department of Cell and Molecular Biology, Pontificia Universidad Católica de Chile, Santiago, Chile; CARE UC Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address: aalvarez@bio.puc.cl.
authors.forename: Alejandra R
authors.initials: AR
authors.lastname: Alvarez
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; FONDAP Center for Genome Regulation (CGR), Santiago, Chile. Electronic address: silvana@med.puc.cl.
authors.forename: Silvana
authors.initials: S
authors.lastname: Zanlungo
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D003505:Cyclodextrins / Q000008:administration & dosage; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D056464:Histone Deacetylase 2 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016315:Proto-Oncogene Proteins c-abl / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage
chemical_list: D003505:Cyclodextrins; D014810:Vitamin E; D002784:Cholesterol; D016315:Proto-Oncogene Proteins c-abl; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: GNF2; Histone deacetylase 2; Imatinib; Neuronal genes; Niemann–Pick type C disease; Tyrosine kinase c-Abl