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Gene expression profiling in frataxin deficient mice: microarray evidence for significant expression changes without
Giovanni Coppola1, Sang-Hyun Choi, Manuela M Santos
1Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine-UCLA, 710 Westwood Plaza, Los Angeles, CA 90095, USA.
Abstract:
Friedreich's ataxia (FRDA) is caused by reduction of frataxin levels to 5-35%. To better understand the biochemical sequelae of frataxin reduction, in absence of the confounding effects of neurodegeneration, we studied the gene expression profile of a mouse model expressing 25-36% of the normal frataxin levels, and not showing a detectable phenotype or neurodegenerative features. Despite having no overt phenotype, a clear microarray gene expression phenotype was observed. This phenotype followed the known regional susceptibility in this disease, most changes occurring in the spinal cord. Additionally, gene ontology analysis identified a clear mitochondrial component, consistent with previous findings. We were able to confirm a subset of changes in fibroblast cell lines from patients. The identification of a core set of genes changing early in the FRDA pathogenesis can be a useful tool in both clarifying the disease process and in evaluating new therapeutic strategies.
Insights
Early gene expression changes in Friedreich's ataxia (FRDA) were identified in a mouse model lacking neurodegeneration. These findings in FRDA pathogenesis may aid in developing new therapeutic strategies.
Area of Science:
- Genetics
- Neurobiology
- Mitochondrial Biology
Background:
- Friedreich's ataxia (FRDA) is characterized by reduced frataxin levels (5-35%).
- Understanding early biochemical changes is crucial, especially without confounding neurodegeneration.
Purpose of the Study:
- To investigate the gene expression profile in a mouse model with partial frataxin reduction (25-36%).
- To identify early molecular alterations in FRDA pathogenesis before overt symptoms or neurodegeneration occur.
Main Methods:
- Utilized microarray analysis to study gene expression in a mouse model of FRDA.
- Performed gene ontology analysis to identify biological pathways affected.
- Confirmed a subset of gene expression changes in patient-derived fibroblast cell lines.
Main Results:
- A distinct gene expression phenotype was observed despite the absence of a detectable phenotype or neurodegeneration.
- Gene expression changes were concentrated in the spinal cord, aligning with known disease susceptibility.
- Gene ontology analysis revealed a significant mitochondrial component, consistent with prior research.
Conclusions:
- Early identification of a core set of altered genes in FRDA pathogenesis is possible.
- These findings provide insights into the disease process and can serve as biomarkers for therapeutic evaluation.
- This research aids in understanding FRDA at a molecular level, independent of neurodegenerative effects.
