PMID- 17565993
OWN - NLM
STAT- MEDLINE
DCOM- 20071011
LR  - 20220129
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 34
DP  - 2007 Aug 24
TI  - Loss of huntingtin function complemented by small molecules acting as repressor 
      element 1/neuron restrictive silencer element silencer modulators.
PG  - 24554-62
AB  - 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.
FAU - Rigamonti, Dorotea
AU  - Rigamonti D
AD  - Centre for Stem Cell Research and Department of Pharmacological Sciences, 
      University of Milan, Via Balzaretti 9, Milan 20133, Italy.
FAU - Bolognini, Daniele
AU  - Bolognini D
FAU - Mutti, Cesare
AU  - Mutti C
FAU - Zuccato, Chiara
AU  - Zuccato C
FAU - Tartari, Marzia
AU  - Tartari M
FAU - Sola, Francesco
AU  - Sola F
FAU - Valenza, Marta
AU  - Valenza M
FAU - Kazantsev, Aleksey G
AU  - Kazantsev AG
FAU - Cattaneo, Elena
AU  - Cattaneo E
LA  - eng
GR  - GGP06250/TI_/Telethon/Italy
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070612
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Htt protein, rat)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Peptides)
RN  - 0 (Transcription Factors)
RN  - EC 1.13.12.- (Luciferases)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cell Survival
MH  - Dose-Response Relationship, Drug
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Gene Expression Regulation
MH  - Gene Silencing
MH  - Huntingtin Protein
MH  - Immunohistochemistry
MH  - Luciferases/metabolism
MH  - Models, Chemical
MH  - Nerve Tissue Proteins/metabolism/*physiology
MH  - Neurons/metabolism
MH  - Nuclear Proteins/metabolism/*physiology
MH  - Peptides/chemistry
MH  - Rats
MH  - Transcription Factors/metabolism
EDAT- 2007/06/15 09:00
MHDA- 2007/10/12 09:00
CRDT- 2007/06/15 09:00
PHST- 2007/06/15 09:00 [pubmed]
PHST- 2007/10/12 09:00 [medline]
PHST- 2007/06/15 09:00 [entrez]
AID - S0021-9258(18)80939-5 [pii]
AID - 10.1074/jbc.M609885200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Aug 24;282(34):24554-62. doi: 10.1074/jbc.M609885200. Epub 2007 
      Jun 12.