A reduction in C9orf72 makes motor neurons more vulnerable to ALS according to a growing number of studies (see February 2018 news). But how the loss of function of this protein contributes to the disease remains hotly debated (see March 2016 news; Zhang et al., 2018).
Now, a research team led by University of Ottawa’s Derrick Gibbings in Canada, propose that a drop in C9orf72 might increase motor neuron toxicity in ALS by blocking the ability of stress granules to be removed from the cytoplasm.
The researchers found that C9orf72, in a complex containing p62, marks stress granules for degradation by binding arginine-methylated proteins including FUS decorating its surfaces – at least in cultured human cells. What’s more, reducing levels of C9orf72 led to the accumulation of stress granules in the cytoplasm.
The results suggest that C9orf72 may trigger the clearance of stress granules by autophagy through a p62-mediated mechanism.
The findings build on previous studies, led by University of Bern’s Smita Saxena in Switzerland, which found that the reduction of C9orf72 in a cellular model of ALS led to an increase in stress granules in the cytoplasm (Maharjan et al., 2017).
The study appeared on July 16 in Nature Communications.
The results suggest that C9orf72 may act as a key fail-safe mechanism that protects cells including neurons by removing aggregation-prone RNA-binding proteins that escape into the cytoplasm.
The results add to growing evidence that restoring levels of C9orf72 may also be needed to treat the disease (see March 2016 news). Efforts to develop therapies for C9orf72 ALS are currently ongoing (see October 2017, December 2017 news).
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