. ALS-associated ataxin 2 polyQ expansions enhance stress-induced caspase 3 activation and increase TDP-43 pathological modifications. J Neurosci. 2012 Jul 4;32(27):9133-42. PubMed.


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  1. I think the overall idea is quite interesting. In a nutshell, it is that TDP-43 normally shuttles between the nucleus and the cytoplasm. Under stress, it moves temporarily to the cytoplasm to form stress granules to help cells cope with the stress. Versions of ataxin-2 with polyQ expansions that are longer than normal but not long enough to cause spinocerebellar ataxia enable it to cooperate with TDP-43 and cause neurodegeneration. Both proteins are involved in stress granule formation, which would be the logical place for an interaction that might cause synergistic toxicity. But there also seems to be a role for activation of caspase-3, which can cleave TDP-43, and presumably promote cell death. The biology is interesting in part because only intermediate polyQ lengths seem to confer these properties—normal polyQ stretches or ones that cause SCA2 don't work.

    Whereas the amount of ALS explained by this biology is probably small, it does give us additional insights into how TDP-43 might work and lead to neurodegeneration. Since TDP-43 pathology is found in a number of neurodegenerative diseases, those insights have broader implications. We had shown a few years ago that ALS-causing mutations in TDP-43 increase its levels in the cytoplasm. The extent to which TDP-43 is in the cytoplasm, whether a disease-causing mutation is present or not, seems to predict whether and when neurons will die. The results of the Gitler paper are consistent with that and suggest a model in which ataxin-2 with intermediate polyQ lengths might lead to an interaction with TPD-43 in the cytoplasm that has the net effect of stabilizing it there. The work provides important insights into the mechanisms by which a genetic modifier might mediate its activities.

    It's too early to tell whether there is a therapeutic angle here. We need to understand the biology better, and the one thing we can say for sure is that the levels and localization of TDP-43 appear to be meticulously and intricately regulated by cells.

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  1. ALS-Linked Ataxin Repeats Stick It to TDP-43 in Stressed Cells