C9orf72 regulates the unfolded protein response and stress granule formation by interacting with eIF2 alpha

Rationale: A C9orf72 hexanucleotide repeat expansion (GGGGCC) is the most common genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Haploinsufficiency of C9orf72 has been proposed as a possible disease mechanism (loss-of-function mechanism). Additionally, the aberrantly activated unfolded protein response (UPR) and stress granule (SG) formation are associated with the etiopathology of both ALS and FTD. However, the molecular determinants in this pathogenesis are not well characterized.Methods: We performed an immunoprecipitation-mass spectrometry (IP-MS) assay to identify potential proteins interacting with the human C9orf72 protein. We used C9orf72 knockout cell and rat models to determine the roles of C9orf72 in translation initiation and the stress response.Results: Here, we show that C9orf72, which is genetically and pathologically related to ALS and FTD, interacts with eukaryotic initiation factor 2 subunit alpha (eIF2 alpha) and regulates its function in translation initiation. C9orf72 knockout weakens the interaction between eIF2 alpha and eIF2B5, leading to global translation inhibition. Moreover, the loss of C9orf72 results in primary ER stress with activated UPR in rat spleens, which is one of the causes of splenomegaly with inflammation in C9orf72-/- rats. Finally, C9orf72 delays SG formation by interacting with eIF2 alpha in stressed cells.Conclusions: In summary, these data reveal that C9orf72 modulates translation initiation, the UPR and SG formation, which have implications for understanding ALS/FTD pathogenesis.

Automated summary

C9orf72 interacts with eIF2 alpha to modulate translation initiation; C9orf72 knockout leads to global translation inhibition and primary ER stress; C9orf72 delays SG formation in stressed cells.