C9orf72 May Help Remove Stress Granules

Clear out. A protein complex containing C9orf72 helps remove stress granules from the cytoplasm by binding key proteins that are symmetrically methylated on arginines – at least in cultured human cells. [Courtesy of Chitiprolu et al., 2018, Nature Communications. CC BY 4.0].

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).

References

Chitiprolu M, Jagow C, Tremblay V, Bondy-Chorney E, Paris G, Savard A, Palidwor G, Barry FA, Zinman L, Keith J, Rogaeva E, Robertson J, Lavallée-Adam M, Woulfe J, Couture JF, Côté J, Gibbings D. A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy. Nat Commun. 2018 Jul 18;9(1):2794. [PubMed].

Maharjan N, Künzli C, Buthey K, Saxena S. C9ORF72 Regulates Stress Granule Formation and Its Deficiency Impairs Stress Granule Assembly, Hypersensitizing Cells to Stress. Mol Neurobiol. 2017 May;54(4):3062-3077. [PubMed].

Further Reading

O’Rourke JG, Bogdanik L, Yáñez A, Lall D, Wolf AJ, Muhammad AK, Ho R, Carmona S, Vit JP, Zarrow J, Kim KJ, Bell S, Harms MB, Miller TM, Dangler CA, Underhill DM, Goodridge HS, Lutz CM, Baloh RH. C9orf72 is required for proper macrophage and microglial function in mice. Science. 2016 Mar 18;351(6279):1324-9. [PubMed].

Webster CP, Smith EF, Bauer CS, Moller A, Hautbergue GM, Ferraiuolo L, Myszczynska MA, Higginbottom A, Walsh MJ, Whitworth AJ, Kaspar BK, Meyer K, Shaw PJ, Grierson AJ, De Vos KJ. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 2016 Aug 1;35(15):1656-76. [PubMed].

Sellier C, Campanari ML, Julie Corbier C, Gaucherot A, Kolb-Cheynel I, Oulad-Abdelghani M, Ruffenach F, Page A, Ciura S, Kabashi E, Charlet-Berguerand N. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 2016 Jun 15;35(12):1276-97. [PubMed].

 

arginine methylation autophagy c9orf72 c9orf72 protein disease-als disease-ftd loss of function p62 PRMT5 stress granules topic-preclinical
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