Loss of Muscleblind Splicing Factor ShortensC. elegansLifespan by Reducing the Activity of p38 MAPK/PMK-1 and Transcription Factors ATF-7 and Nrf/SKN-1
| Autor: | Jens Verbeeren, Ruslan I. Sadreyev, Murat Cetinbas, Susana M. D. A. Garcia, Ana R. S. Ribeiro, Olli Matilainen |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Gene knockdown ved/biology Alternative splicing ved/biology.organism_classification_rank.species Biology biology.organism_classification medicine.disease Myotonic dystrophy Cell biology 03 medical and health sciences Splicing factor 0302 clinical medicine RNA splicing medicine Model organism Transcription factor 030217 neurology & neurosurgery Caenorhabditis elegans 030304 developmental biology |
| Popis: | Muscleblind-like splicing regulators (MBNLs) are alternative splicing factors that have an important role in developmental processes. Dysfunction of these factors is a key contributor of different neuromuscular degenerative disorders, including Myotonic Dystrophy type 1 (DM1). Since DM1 is a multisystemic disease characterized by symptoms resembling accelerated aging, we asked whether MBNLs regulate cellular processes required to maintain normal lifespan. By utilizing the model organismCaenorhabditis elegans, we found that loss of MBL-1 (the sole ortholog of mammalian MBNLs), which is known to be required for normal lifespan, shortens lifespan by decreasing the activity of p38 MAPK/PMK-1 as well as the function of transcription factors ATF-7 and SKN-1. Furthermore, we show that mitochondrial stress caused by knockdown of mitochondrial electron transport chain components promotes the longevity ofmbl-1mutants in a partially PMK-1-dependent manner. Together, the data establish a mechanism of how DM1-associated loss of muscleblind affects lifespan. Furthermore, this study suggests that mitochondrial stress could alleviate symptoms caused by the dysfunction of muscleblind splicing factor, creating a potential approach to investigate for therapy.Reviewer token for the RNA-seq data (GEO: GSE146801):wvataksittaffcj |
| Databáze: | OpenAIRE |
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