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- Title
c-Jun N-Terminal Kinase Promotes Stress Granule Assembly and Neurodegeneration in C9orf72-Mediated ALS and FTD.
- Authors
Sahana, Talanjeri Gopalakrishna; Chase, Katherine Johnson; Feilin Liu; Lloyd, Thomas E.; Rossoll, Wilfried; Ke Zhang
- Abstract
Stress granules are the RNA/protein condensates assembled in the cells under stress. They play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how stress granule assembly is regulated and related to ALS/FTD pathomechanism is incompletely understood. Mutation in the C9orf72 gene is the most common cause of familial ALS and FTD. C9orf72 mutation causes the formation of toxic dipeptide repeats. Here we show that the two most toxic dipeptide repeats [i.e., poly(GR) and poly(PR)] activate c-Jun N-terminal kinase (JNK) via the ERstress response protein IRE1 using fly and cellular models. Further, we show that activated JNK promotes stress granule assembly in cells by promoting the transcription of one of the key stress granule proteins (i.e., G3BP1) by inducing histone 3 phosphorylation. Consistent with these findings, JNK or IRE1 inhibition reduced stress granule formation, histone 3 phosphorylation, G3BP1 mRNA and protein levels, and neurotoxicity in cells overexpressing poly(GR) and poly(PR) or neurons derived from male and female C9ALS/FTD patient-induced pluripotent stem cells. Our findings connect ER stress, JNK activation, and stress granule assembly in a unified pathway contributing to C9ALS/FTD neurodegeneration.
- Subjects
AMYOTROPHIC lateral sclerosis; PLURIPOTENT stem cells; GRANULE cells; HEAT shock proteins; NEURODEGENERATION; RILUZOLE
- Publication
Journal of Neuroscience, 2023, Vol 43, Issue 17, p3186
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1799-22.2023