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C-Jun N-terminal Kinase Promotes Stress Granule Assembly and Neurodegeneration in C9orf72-mediated ALS and FTD

TG, S.; Chase, K. J.; Liu, F.; Lloyd, T. E.; Rossoll, W.; Zhang, K.

2022-04-29 neuroscience
10.1101/2022.04.28.489917 bioRxiv
Show abstract

Stress granules (SGs), RNA/protein condensates assembled in cells under stress, are believed to play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how SG assembly is regulated and related to pathomechanism is incompletely understood. Here, we show that ER stress activates JNK via IRE1 in fly and cellular models of C9orf72-mediated ALS/FTD (c9ALS/FTD), the most common genetic form of ALS/FTD. Furthermore, activated JNK promotes SG assembly induced by poly(GR) and poly(PR), two toxic proteins implicated in c9ALS/FTD, by promoting the transcription of G3BP1, a key SG protein. Consistent with these findings, JNK or IRE1 inhibition reduced SG formation, G3BP1 mRNA and protein levels, and neurotoxicity in cells overexpressing poly(GR) and poly(PR) or neurons derived from c9ALS/FTD patient induced pluripotent stem cells (iPSCs). Our findings connect ER stress, JNK, and SG assembly in a unified pathway contributing to c9ALS/FTD neurodegeneration.

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