Genetic modifiers in drosophilia models of HD and SCA1

HD Lighthouse Contributing Editor's Comment: 

The search for genetic modifiers is very important. We know that two people with the same CAG count can have widely different ages of onset. Some of the difference is undoubtedly accounted for by environmental factors but some of it is a result of different genes that might speed or delay onset. Discovering these genes should provide leads in the search for treatments.

Researchers looked for genetic modifiers in HD and in SCA1, using fruitfly models of these diseases. Since both are CAG repeat diseases, it is not surprising that there are a number of genetic modifiers in common. What is very interesting, however, is that some modifiers work in oppositive directions, speeding onset in one disease, while delaying it in others. Looking more closely at the role of these genes in each disease should lead to insights into both diseases and how they might be treated.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 12-29-2007

Juan Botas, Ph.D.

Comparative Analysis of Genetic Modifiers in Drosophila Points to Common and Distinct Mechanisms of Pathogenesis among Polyglutamine Diseases

Joana Branco, Ismael Al-Ramahi, Lubna Ukani, Alma M. Pérez, Pedro Fernandez-Funez, Diego Rincón-Limas and Juan Botas

press release: Similarities between genetic diseases create hope for treatment

HOUSTON -- (December 27, 2007) -- Two rare neurodegenerative diseases -- Huntington's disease and spinocerebellar ataxia 1 – share genetic modifiers in the cellular pathways that cause nerve cell damage, a fact that may make studying them and developing treatments more attractive to biotech companies, said a Baylor College of Medicine researcher.

A report on the research led by Dr. Juan Botas, associate professor of molecular and human genetics at BCM, appears in the current issue of the journal Human Molecular Genetics.

"We found commonalities in the diseases," he said. "These diseases are not like Alzheimer's disease or Parkinson's, which affect many patients. Often these rarer diseases get less attention in the media or from pharmaceutical companies, but they are no less devastating."

Symptoms of both these diseases show up in adulthood. They are both polyglutamine disorders. Expansion of DNA repeats encoding glutamine within the genes for each disease – ataxin-1 for the ataxia and huntingtin for Huntington's – spell disaster for how the protein is used by the cell. While studies indicate that the repeats interfere with the proper folding of the proteins encoded by the genes, other research indicates that other factors specific to each disease are involved.

When Botas and his colleagues compared the two diseases in models in Drosophila, or fruit flies, they found that some genes that modify the neuronal toxicity of ataxin-1 and huntingtin function similarly in both insect models of the diseases. In contrast, others have opposite effects, suppressing toxicity in one case and enhancing it in another.

Some of the genes that they found affect RNA (ribonucleic acid) metabolism, or its production, modulating the toxic effect of the proteins ataxin and huntingtin on nerve cells.

The genes that have opposite effects on the neuronal toxicity of ataxin-1 and huntingtin might help identify differences in how the two proteins affect nerve cells negatively, he said.

The modifier genes ameliorating the neuronal toxicity of both ataxin-1 and huntingtin, and their corresponding cellular pathways, might point to targets for drugs in both diseases, said Botas.

Others who took part in this research include Joana Branco, Ismael Al-Ramahi, Lubna Ukani, Alma M. Perez, Pedro Fernandez-Funez and Diego Rincón-Lima, all of BCM. Funding for this work came from the National Institutes of Health and the Portuguese Foundation for Science and Technology.

journal abstract

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.

Source: Human Molecular Genetics Advance Access published on November 5, 2007