Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases

Spinocerebellar Ataxia type 1 (SCA1) and Huntington's disease (HD) are two polyglutamine disorders caused by expansion of a CAG repeat within the coding regions of the Ataxin-1 and Huntingtin proteins, respectively. While protein folding and turnover have been implicated in polyglutamine disord...

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Bibliographic Details
Published in:Human molecular genetics 2008-02, Vol.17 (3), p.376-390
Main Authors: Branco, Joana, Al-Ramahi, Ismael, Ukani, Lubna, Pérez, Alma M., Fernandez-Funez, Pedro, Rincón-Limas, Diego, Botas, Juan
Format: Article
Language:English
Subjects:
Animals
Animals, Genetically Modified
Ataxin-1
Ataxins
Biological and medical sciences
Disease Models, Animal
Drosophila
Drosophila - genetics
Drosophila Proteins - genetics
Fundamental and applied biological sciences. Psychology
Genes, Dominant
Genes, Insect
Genetics of eukaryotes. Biological and molecular evolution
Heredodegenerative Disorders, Nervous System - etiology
Heredodegenerative Disorders, Nervous System - genetics
Humans
Huntingtin Protein
Huntington Disease - etiology
Huntington Disease - genetics
Molecular and cellular biology
Nerve Tissue Proteins - genetics
Nuclear Proteins - genetics
Peptides - genetics
Phenotype
Phospholipid Transfer Proteins - genetics
Proto-Oncogene Proteins c-akt - genetics
Recombinant Proteins - genetics
Spinocerebellar Ataxias - etiology
Spinocerebellar Ataxias - genetics
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Summary:Spinocerebellar Ataxia type 1 (SCA1) and Huntington's disease (HD) are two polyglutamine disorders caused by expansion of a CAG repeat within the coding regions of the Ataxin-1 and Huntingtin proteins, respectively. While protein folding and turnover have been implicated in polyglutamine disorders in general, many clinical and pathological differences suggest that there are also disease-specific mechanisms. Taking advantage of a collection of genetic modifiers of expanded Ataxin-1-induced neurotoxicity, we performed a comparative analysis in Drosophila models of the two diseases. We show that while some modifier genes function similarly in SCA1 and HD Drosophila models, others have model-specific effects. Surprisingly, certain modifier genes modify SCA1 and HD models in opposite directions, i.e. they behave as suppressors in one case and enhancers in the other. Furthermore, we find that modulation of toxicity does not correlate with alterations in the formation of neuronal intranuclear inclusions. Our results point to potential common therapeutic targets in novel pathways, and to genes and pathways responsible for differences between Ataxin-1 and Huntingtin-induced neurodegeneration.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddm315