. Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis. Arch Neurol. 2011 Jun;68(6):739-42. PubMed.


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  1. Several recent studies have evaluated the role of ataxin 2 in independent ALS patient populations worldwide and have found an association with polyglutamine repeat expansions and risk for the disease, confirming and extending the initial findings by Nancy Bonini's and my laboratories last year (Elden et al., 2010). The specific cutoff of polyQ length and risk for ALS seem to vary from population to population, with longer polyQ repeat lengths having a more significant effect on ALS risk. It has been appreciated that SCA2 and ALS can share some similar clinical features; Some SCA2 patients present with prominent motor neuron signs. These genetic studies now also point to the idea that SCA2 and ALS could share similar molecular and genetic underpinnings. The challenge now will be to define the cellular mechanisms by which polyQ expansions in ataxin 2 contribute to risk for ALS. Also, what is the mechanism by which long polyQ repeats (>34Q) in ataxin 2 lead to SCA2, whereas intermediate-length ataxin 2 polyQ expansions (e.g., 27-33Q) are associated with ALS. One simple explanation could be that cerebellar Purkinje neurons are more "resistant" to ataxin 2 polyQ expansions than motor neurons and thus require longer expansions in order to cause degeneration. But if this were the case, it would predict that all SCA2 patients would present with prominent motor neuron degeneration. Therefore, the differential effects of long versus intermediate-length polyQ expansions are likely more complicated and need to be explored in more detail.

    The study by Rademakers and colleagues (Ross et al., 2011) also suggests ataxin 2 polyQ expansions increase risk of progressive supranuclear palsy (PSP), which is a tauopathy, so it will be important to determine if and how ataxin 2 interacts with tau and what role this plays in disease. Our recent study evaluating other polyQ disease genes in ALS (Lee et al., 2011) did not find expansions in other polyQ disease genes (e.g., huntingtin, ataxin 1, ataxin 3, etc.), suggesting that the effect of ataxin 2 polyQ expansions on ALS risk is probably caused by an enhancement or perturbation of ataxin 2's normal function, probably in RNA metabolism, and not because of the polyQ stretch per se.


    . Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. PubMed.

    . Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet. 2011 Aug 15;20(16):3207-12. PubMed.

    . Evaluating the prevalence of polyglutamine repeat expansions in amyotrophic lateral sclerosis. Neurology. 2011 Jun 14;76(24):2062-5. PubMed.

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