In the decade since human genes associated with neurodegenerative disease were first used in flies to create pathological phenotypes [1–5], a minor industry has sprung up using flies as a model to study the mechanisms underlying central nervous system malfunction in humans. Why study neurodegeneration in flies? Their small size, rapid generation time, and low costs for maintenance as compared to mammalian models make them attractive enough. The true value of flies to the study of neurodegenerative disorders, however, is their capacity to provide a platform for unbiased genetic screens to identify components of pathological pathways. If expression of pathological human genes in the fly successfully generates an abnormal phenotype, such as slowed motor activity or degeneration of the retina, this phenotype can then be used in conjunction with the rich genetic toolbox that Drosophila researchers have developed over the last 90 years to identify pathways that contribute to this degeneration. This approach is unbiased, i.e., it does not depend upon prior assumptions about mechanisms underlying disease, and genome-wide screens can be carried out in the fly that would be difficult if not impossible to carry out using mouse models. Key to such an approach is how similar flies are to humans. A stunning 75% (approximately) of the genes implicated in human genetic disorders have at least one homolog in the fruit fly (see http://superfly.ucsd.edu/homophila/ for further information). In general, fundamental aspects of cell biology relevant to processes as diverse as cell cycle regulation, synaptogenesis, membrane trafficking, and cell death are similar in Drosophila and humans. Of course, there are important differences between flies and humans; for example, the circulatory system is much simpler in the fly, and cognitive processes are much less complex. Nonetheless, the fly has proved itself as a useful adjunct to mammalian models for neurodegenerative diseases. A variety of neurodegenerative disorders have been modeled in the fly (for reviews, see [6–10]); perhaps the best established and most robust models are those associated with a group of inherited disorders that are all caused by the same mechanism: expansion of an unstable CAG repeat resulting in expression of proteins containing expanded polyglutamine tracts. The best known of these disorders is Huntington disease, but there are a number of somewhat similar disorders also caused by a CAG repeat expansion that are collectively referred to as the spinocerebellar ataxias (SCAs). These are generally adult-onset, progressive neurodegenerative disorders that feature impaired coordination due to degeneration of the cerebellum [11]. The different SCAs may have slightly different symptoms in addition to impaired coordination, such as tremor in SCA type 2 (SCA2) similar to that seen in Parkinson disease or muscular atrophy due to nerve damage in SCA3, but all are inexorably progressive. Some symptoms, such as impaired swallowing or gait ataxias, may be mildly improved by medications, assistive devices, or physical therapy, but no disease-modifying treatments exist. The proteins in which the polyglutamine expansions occur in each disorder show no obvious similarities and are referred to as ataxins 1, 2, 3, etc. (Atx1, Atx2, Atx3, etc.). Although the syndromic classifications of neurodegenerative disorders that began to be developed in the nineteenth century focused on distinctions between different disorders, more recent pathological and molecular analyses have begun to identify commonalities between what have traditionally been thought of as distinct diseases, as well as crosstalk between seemingly unrelated disease-associated proteins. In this issue of PLoS Biology, Derek Lessing and Nancy Bonini describe an interaction in which Atx2 contributes to the pathogenicity of Atx3 [12]. This report comes on the heels of similar work by Juan Botas and colleagues describing an interaction between Atx2 and Atx1 [13]. Here, I set out to demystify the creation and deployment of fly models of neurodegenerative diseases, and to put the current studies of interaction among ataxins in perspective.
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Dec 1, 2013
Abba Malina + 8
Open Access
