Neuronal gene repression in Niemann-Pick type C models is mediated by the c-Abl/HDAC2 signaling pathway.

Therapeutic Approaches

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. CONCLUSION: 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

Contreras, Pablo S; Gonzalez-Zuñiga, Marcelo; González-Hódar, Lila; Yáñez, María José; Dulcey, Andrés; Marugan, Juan; Seto, Edward; Alvarez, Alejandra R; Zanlungo, Silvana;

Keywords

  • Animals
  • Cholesterol/ genetics
  • Cholesterol/ metabolism
  • Cyclodextrins/ administration & dosage
  • Disease Models, Animal
  • Gene Expression Regulation/ drug effects
  • Histone Deacetylase 2/ biosynthesis
  • Histone Deacetylase 2/ genetics
  • Humans
  • Lysosomes/ metabolism
  • Mice
  • Neurons/ metabolism
  • Neurons/ pathology
  • Niemann-Pick Disease, Type C/ drug therapy
  • Niemann-Pick Disease, Type C/ genetics
  • Niemann-Pick Disease, Type C/ pathology
  • Proto-Oncogene Proteins c-abl/ biosynthesis
  • Proto-Oncogene Proteins c-abl/ genetics
  • Signal Transduction/ drug effects
  • Vitamin E/ administration & dosage

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