Loss of huntingtin function complemented by small molecules acting as repressor element 1/neuron restrictive silencer element silencer modulators

Dorotea Rigamonti, Daniele Bolognini, Cesare Mutti, Chiara Zuccato, Marzia Tartari, Francesco Sola, Marta Valenza, Aleksey G Kazantsev, Elena Cattaneo

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Increased levels of the repressor element 1/neuron restrictive silencer element (RE1/NRSE) silencing activity promoter, and a consequent reduction in the transcription of many RE1/NRSE-bearing neuronal genes, including brain-derived neurotrophic factor (BDNF), have been demonstrated in Huntington disease (HD) and represent one possible effector of its selective neuronal vulnerability. Restoring the expression levels of neuronal genes in diseased neurons therefore seems to be an attractive therapeutic approach. To this end, we have developed a cell-based reporter assay for monitoring RE1/NRSE silencing activity and validated it by genetically inactivating the RE1/NRSE or pharmacologically stimulating global transcription. In a pilot compound screen, we identified three closely related structural analogues that up-regulate reporter expression at low nanomolar concentrations, and follow-up studies have shown that they efficaciously increase endogenous BDNF levels in HD cells. Moreover, one of the compounds increases the viability of HD cells. Our findings suggest a new avenue for the development of drugs for HD and other neurodegenerative disorders based on the pharmacological up-regulation of the production of the neuronal survival factor BDNF and of other RE1/NRSE-regulated neuronal genes.
Original languageEnglish
Pages (from-to)24554-24562
Number of pages9
JournalThe Journal of Biological Chemistry
Volume282
Issue number34
Early online date12 Jun 2007
DOIs
Publication statusPublished - 24 Aug 2007

Keywords

  • Animals
  • Brain-Derived Neurotrophic Factor
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation
  • Gene Silencing
  • Immunohistochemistry
  • Luciferases
  • Models, Chemical
  • Nerve Tissue Proteins
  • Neurons
  • Nuclear Proteins
  • Peptides
  • Rats
  • Transcription Factors

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  • Cite this

    Rigamonti, D., Bolognini, D., Mutti, C., Zuccato, C., Tartari, M., Sola, F., Valenza, M., Kazantsev, A. G., & Cattaneo, E. (2007). Loss of huntingtin function complemented by small molecules acting as repressor element 1/neuron restrictive silencer element silencer modulators. The Journal of Biological Chemistry, 282(34), 24554-24562. https://doi.org/10.1074/jbc.M609885200