RESUMEN
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 ER-stress 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.SIGNIFICANCE STATEMENT c-Jun N-terminal kinase (JNK) is a part of the mitogen-activated protein kinase pathway, which is the central node for the integration of multiple stress signals. Cells are under constant stress in neurodegenerative diseases, and how these cells respond to stress signals is a critical factor in determining their survival or death. Previous studies have shown JNK as a major contributor to cellular apoptosis. Here, we show the role of JNK in stress granule assembly. We identify that toxic dipeptide repeats produced in ALS/FTD conditions activate JNK. The activated JNK in the nucleus can induce histone modifications which increase G3BP1 expression, thus promoting stress granule assembly and neurodegeneration.
Asunto(s)
Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Femenino , Humanos , Masculino , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Proteína C9orf72/genética , Dipéptidos/genética , Dipéptidos/metabolismo , ADN Helicasas/metabolismo , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Histonas , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN , Gránulos de Estrés , Drosophila melanogaster , AnimalesRESUMEN
Diabetes is a global disease, and its prevalence has increased rapidly in the last century. Many complications are associated with diabetes, and diabetic foot ulcers (DFU) are common. There is a variety of different treatments for DFU, and the aim of this article is to discuss the factors responsible for delayed wound healing in patients with diabetes, and the treatment strategies that are available.