. Proteasome activator enhances survival of Huntington's disease neuronal model cells. PLoS One. 2007;2(2):e238. PubMed.


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  1. The idea that proteasome dysfunction occurs in several neurodegenerative disorders has received quite a lot of attention in recent years. The strength of evidence varies between diseases, but the evidence in Huntington disease (HD) is reasonably strong. For example, genes for proteasome components modulate huntingtin toxicity in yeast but do not affect the toxicity of α-synuclein (Willingham et al., 2003). However, translating this to mammalian systems, and, hence, addressing whether proteasome dysfunction is an important part of the disease process in HD, has been less successful. For example, there are negative results reported, such as the lack of effect of the proteasome activator PA28γ in the R6/2 HD mice (Bett et al., 2006). In this study, Seo et al. report positive effects of increasing expression of PA28γ on cell viability in HD models. This is potentially exciting as it supports the idea that the proteasome might be a therapeutic target for HD, and perhaps for other neurodegenerative disorders. But, why is the evidence for proteasome involvement strong in cells (and in yeast) but weaker in the R6/2 mice?

    One reason Seo et al. discuss is that the R6/2 mice differ from end-stage HD in that the former have increased proteasome activity compared to decreased activity in the latter. This suggests that the model system might not go far enough in modeling the disease, especially its later stages. Of course, the later stages include dramatic cell loss, which might also be a confound for proteasome measurements, but the same investigators have shown previously that the proteasome deficit is seen in early disease stages and outside of the brain (Seo et al., 2004). So to test the hypothesis further, such as in vivo, one would need a model with decreased proteasome function where PA28γ expression could be modulated, something that is apparently true in YAC HD mice.

    Therefore, it might be feasible to establish whether the proteasome plays a role in HD and support the hypothesis that there is the possibility for disease modification. But, to my mind, this still leaves somewhat open the question of when proteasome inhibition contributes to HD (and even more so in other neurodegenerative disorders). The R6/2 mice, with no proteasome impairment, still have neurological phenotypes suggesting that proteasome inhibition is not a necessary component of disease. Perhaps the proteasome dysfunction is a later event in the disease course. Therefore, establishing whether PA28γ can modulate progression at different time courses in the disease will be an interesting and important question for the future.


    . Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein. Science. 2003 Dec 5;302(5651):1769-72. PubMed.

    . Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington's disease mice: exclusion of proteasome activator REGgamma as a therapeutic target. Hum Mol Genet. 2006 Jan 1;15(1):33-44. PubMed.

    . Generalized brain and skin proteasome inhibition in Huntington's disease. Ann Neurol. 2004 Sep;56(3):319-28. PubMed.

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