Document Detail

Altered lipid metabolism in a Drosophila model of Friedreich's ataxia.
MedLine Citation:
PMID:  20460268     Owner:  NLM     Status:  MEDLINE    
Friedreich's ataxia (FRDA) is the most common form of autosomal recessive ataxia caused by a deficit in the mitochondrial protein frataxin. Although demyelination is a common symptom in FRDA patients, no multicellular model has yet been developed to study the involvement of glial cells in FRDA. Using the recently established RNAi lines for targeted suppression of frataxin in Drosophila, we were able to study the effects of general versus glial-specific frataxin downregulation. In particular, we wanted to study the interplay between lowered frataxin content, lipid accumulation and peroxidation and the consequences of these effects on the sensitivity to oxidative stress and fly fitness. Interestingly, ubiquitous frataxin reduction leads to an increase in fatty acids catalyzing an enhancement of lipid peroxidation levels, elevating the intracellular toxic potential. Specific loss of frataxin in glial cells triggers a similar phenotype which can be visualized by accumulating lipid droplets in glial cells. This phenotype is associated with a reduced lifespan, an increased sensitivity to oxidative insult, neurodegenerative effects and a serious impairment of locomotor activity. These symptoms fit very well with our observation of an increase in intracellular toxicity by lipid peroxides. Interestingly, co-expression of a Drosophila apolipoprotein D ortholog (glial lazarillo) has a strong protective effect in our frataxin models, mainly by controlling the level of lipid peroxidation. Our results clearly support a strong involvement of glial cells and lipid peroxidation in the generation of FRDA-like symptoms.
Juan A Navarro; Elisabeth Ohmann; Diego Sanchez; José A Botella; Gerhard Liebisch; María D Moltó; María D Ganfornina; Gerd Schmitz; Stephan Schneuwly
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-10
Journal Detail:
Title:  Human molecular genetics     Volume:  19     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-30     Completed Date:  2010-09-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  2828-40     Citation Subset:  IM    
Institute of Zoology, Universitaetsstrasse 31, University of Regensburg, 93040 Regensburg, Germany.
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MeSH Terms
Animals, Genetically Modified
Carrier Proteins / genetics,  physiology
Cell Survival / genetics
Disease Models, Animal*
Drosophila* / genetics
Drosophila Proteins / genetics,  physiology
Fatty Acids / blood
Friedreich Ataxia / complications,  genetics*,  metabolism,  pathology*
Iron-Binding Proteins / genetics,  metabolism,  physiology
Lipid Metabolism Disorders / complications*,  genetics,  metabolism,  pathology
Lipid Peroxidation / genetics,  physiology
Membrane Glycoproteins / genetics,  physiology
Nervous System / metabolism,  pathology
Neuroglia / metabolism,  physiology
Oxidative Stress / genetics,  physiology
Reg. No./Substance:
0/Carrier Proteins; 0/Drosophila Proteins; 0/Fatty Acids; 0/Glial Lazarillo protein, Drosophila; 0/Iron-Binding Proteins; 0/Membrane Glycoproteins; 0/frataxin

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