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Silencing of frataxin gene expression triggers p53-dependent apoptosis in human neuron-like cells.
MedLine Citation:
PMID:  21531789     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Friedreich's ataxia is an autosomal recessive disease caused by mutations that produce a deficiency in frataxin. Despite of the importance of neurodegeneration in Friedreich's ataxia, little is known about the consequences of frataxin deficit in neuronal cells. Here we describe a neuronal cell model for Friedreich's ataxia based on the use of lentiviral vectors that carry minigenes encoding frataxin-specific shRNAs that silence the expression of this gene. These lentivectors can knockdown frataxin expression in human neuroblastoma SH-SY5Y cells, which results in large-scale cell death in differentiated neuron-like cells but not in undifferentiated neuroblastoma cells. Frataxin-deficient neuron-like cells appear to die through apoptosis which is accompanied by up-regulation of p53, PUMA and Bax and activation of caspase-3. No significant autophagy is observed in frataxin-deficient neuron-like cells and the pharmacological activation of autophagy does not significantly increase neuronal cell death in response to the frataxin deficit. Cell death triggered by frataxin knockdown can be impaired by interference with p53, caspase inhibitors and gene transfer of frataxin. These results suggest that frataxin gene silencing in human neuron-like cells may constitute a useful cell model to characterise the molecular changes triggered by frataxin deficiency in neurons, as well as to search for therapies that may protect against neurodegeneration.
Authors:
Gloria M Palomo; Toñi Cerrato; Ricardo Gargini; Javier Díaz-Nido
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-4-29
Journal Detail:
Title:  Human molecular genetics     Volume:  -     ISSN:  1460-2083     ISO Abbreviation:  -     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-5-2     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), C/ Nicolás Cabrera, 1. Campus de Cantoblanco. Universidad Autónoma de Madrid. 28049 Madrid, Spain.
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