Allele-Specific Silencing of Mutant Huntingtin in Rodent Brain and Human Stem Cells

Autor: Raymonde Hassig, Diana Zala, Laetitia Troquier, Johann Carpentier, Maxime Feyeux, Sophie Aubert, Karine Cambon, Nicolas Merienne, Anselme L. Perrier, Maria Rey, Nicole Déglon, Gwennaelle Auregan, Fany Bourgois-Rocha, Valérie Drouet, Marta Ruiz, Frédéric Saudou, Noelle Dufour, Philippe Hantraye
Přispěvatelé: Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2014
Předmět:
Male
Huntingtin
RNA Stability
[SDV]Life Sciences [q-bio]
animal diseases
Mutant
lcsh:Medicine
Mice
RNA interference
Trinucleotide Repeats
RNA Isoforms
RNA
Small Interfering
lcsh:Science
Cells
Cultured
ComputingMilieux_MISCELLANEOUS
Huntingtin Protein
Plasmid Vectors
Multidisciplinary
Brain
3. Good health
Huntington Disease
Genetic Engineering
Research Article
Biotechnology
congenital
hereditary
and neonatal diseases and abnormalities
Nerve Tissue Proteins
In Vitro Techniques
Biology
Polymorphism
Single Nucleotide
Molecular Genetics
mental disorders
Genetics
Animals
Humans
Gene Disruption
Gene silencing
Rats
Wistar
Molecular Biology
Embryonic Stem Cells
Biology and life sciences
lcsh:R
HEK 293 cells
Wild type
RNA
Genetic Therapy
Molecular biology
Rats
nervous system diseases
Disease Models
Animal
HEK293 Cells
nervous system
Mutation
Mutant Proteins
lcsh:Q
Gene expression
Molecular Neuroscience
Neuroscience
Zdroj: PLoS ONE, Vol 9, Iss 6, p e99341 (2014)
PLoS ONE
PLoS ONE, 2014, 9 (6), pp.e99341. ⟨10.1371/journal.pone.0099341⟩
PLoS ONE, Public Library of Science, 2014, 9 (6), pp.e99341. ⟨10.1371/journal.pone.0099341⟩
Plos One, vol. 9, no. 6, pp. e99341
PloS one
ISSN: 1932-6203
Popis: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from polyglutamine expansion in the huntingtin (HTT) protein and for which there is no cure. Although suppression of both wild type and mutant HTT expression by RNA interference is a promising therapeutic strategy, a selective silencing of mutant HTT represents the safest approach preserving WT HTT expression and functions. We developed small hairpin RNAs (shRNAs) targeting single nucleotide polymorphisms (SNP) present in the HTT gene to selectively target the disease HTT isoform. Most of these shRNAs silenced, efficiently and selectively, mutant HTT in vitro. Lentiviral-mediated infection with the shRNAs led to selective degradation of mutant HTT mRNA and prevented the apparition of neuropathology in HD rat's striatum expressing mutant HTT containing the various SNPs. In transgenic BACHD mice, the mutant HTT allele was also silenced by this approach, further demonstrating the potential for allele-specific silencing. Finally, the allele-specific silencing of mutant HTT in human embryonic stem cells was accompanied by functional recovery of the vesicular transport of BDNF along microtubules. These findings provide evidence of the therapeutic potential of allele-specific RNA interference for HD.
Databáze: OpenAIRE
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