. Survival from hypoxia in C. elegans by inactivation of aminoacyl-tRNA synthetases. Science. 2009 Jan 30;323(5914):630-3. PubMed.

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  1. This is a fascinating paper. It presents a strong case that normal translation of proteins under hypoxic conditions can lead to cell death, and that reducing protein synthesis can therefore be protective when oxygen (and probably glucose, too) is limiting. This effect appears to be caused by the accumulation of misfolded proteins, which can disrupt the normal function of cellular processes. If the cell can reduce translation in that situation, it decreases the accumulation of toxic misfolded proteins. That makes a lot of sense. The data here indicate a more general translational effect, since the knockdown of most aminoacyl-tRNA synthetases had the same effect on reducing translation and protecting against hypoxia.

    Similar mechanisms may be at play in Alzheimer disease, if chronic reduction in energy supply or metabolism is occurring in the disease. Reduced oxygen and/or glucose would be expected to increase the accumulation of misfolded proteins and lead to cell toxicity in AD. The increase in phosphorylated eIF2α that we observe indicates the unfolded protein response is at least partially activated in AD and APP transgenic brain (O’Connor et al., 2008). This would be expected to reduce general translation of proteins, but increase specific stress response protein synthesis such as BACE1. Perhaps this is the AD brain trying to protect itself against misfolded protein toxicity. If this pathway becomes deficient with age in AD, perhaps neuron dysfunction and loss is the result. Time (and more research) will tell!

    References:

    . Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron. 2008 Dec 26;60(6):988-1009. PubMed.