Polyglutamine Genes Interact To Modulate The Severity And Progression Of Neurodegeneration In Drosophila

Main Category: Neurology / Neuroscience
Also Included In: Genetics;  Biology / Biochemistry
Article Date: 11 Feb 2008 - 17:00 PDT

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Six forms of spinal cerebellar ataxia (SCA1, 2, 3, 6, 7, and 17) are caused by dominant mutations in the respective genes. Patients suffering from these different forms of SCA have similar symptoms of progressive adult-onset neurodegeneration, and the same causative mutation, a CAG repeat expansion encoding an expanded run of polyglutamine. While the affected proteins are distinct and share no sequence similarity beyond the polyglutamine domains, clinical and other observations hint at interactions between the genes that cause different forms of SCA.

This week in the open-access journal PLoS Biology, Derek Lessing and Nancy Bonini show how using Drosophila as a model for human disease, they can now detail an interaction between the genes associated with SCA3 and SCA2. They find that toxicity and neurodegeneration induced by pathogenic forms of SCA3 depends on the normal activity of the fly counterpart of the gene associated with SCA2, ataxin-2. This interaction depends on a conserved protein-interaction motif of Ataxin-2, and a protein that binds this motif, cytoplasmic poly(A)-binding protein (PABP), also modulates SCA3 degeneration.

These results suggest that the normal roles of Ataxin-2 and PABP, potentially to regulate the translation of select target mRNAs, are critical to SCA3 disease. These studies also highlight how a fly model can serve to enhance and extend intriguing clinical findings of the human disease.

Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila
Lessing D, Bonini NM
PLoS Biol 6(2): e29. doi:10.1371/journal.pbio.0060029
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