Loss of huntingtin function complemented by small molecules acting as repressor element 1/neuron restrictive silencer element silencer modulators.
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.
Rigamonti
Dorotea
D
Centre for Stem Cell Research and Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan 20133, Italy.
Bolognini
Daniele
D
Mutti
Cesare
C
Zuccato
Chiara
C
Tartari
Marzia
M
Sola
Francesco
F
Valenza
Marta
M
Kazantsev
Aleksey G
AG
Cattaneo
Elena
E
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D020868:Gene Silencing; D000071058:Huntingtin Protein; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D008956:Models, Chemical; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D010455:Peptides / Q000737:chemistry; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D014157:Transcription Factors; D008156:Luciferases