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In vivo delivery of DN:REST improves transcriptional changes of REST-regulated genes in HD mice.
MedLine Citation:
PMID:  23151521     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Current therapeutic strategies for Huntington's disease (HD) are focused on symptom management of disease progression. Transcriptional dysregulation is one of the major characteristics in HD. REST is a transcriptional repressor that silences gene expression through binding to RE1/NRSE sites found in the regulatory regions of numerous neuronal genes. Dysregulation of REST and its targeted genes has been reported in different cell and mouse HD models, as well as in biopsies from human patients. In this work, we characterized transcriptional dysregulation associated with REST in two different HD mouse models and assessed the therapeutic effect of interfering with REST function by overexpressing a dominant-negative form (DN:REST). We show that delivery of DN:REST in the motor cortex restores brain-derived neurotrophic factor (BDNF) mRNA and protein levels by reducing endogenous REST occupancy at the Bdnf locus. Similarly, expression of other REST-regulated genes such as Synapsin I (Syn1), Proenkephalin (Penk1) and Cholinergic receptor muscarinic 4 (Chrm4) were restored to normal levels while non-REST-regulated genes were unaffected. This is the first study conducted to investigate REST's role in vivo in a neurodegenerative disease. Our data show that DN:REST in motor cortex reversed RESTs repressive effects on target genes. However, the lack of therapeutic effect on motor function suggests that a more widespread rescue of REST-regulated sites in the affected brain regions may be necessary.Gene Therapy advance online publication, 15 November 2012; doi:10.1038/gt.2012.84.
Authors:
P Conforti; A Mas Monteys; C Zuccato; N J Buckley; B Davidson; E Cattaneo
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-15
Journal Detail:
Title:  Gene therapy     Volume:  -     ISSN:  1476-5462     ISO Abbreviation:  Gene Ther.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421525     Medline TA:  Gene Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Center for Stem Cell Research, Università degli Studi di Milano, Milan, Italy.
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