Document Type
Article
Publication Date
8-6-2024
Abstract
Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.
Recommended Citation
M Rebecca Glineburg, Evrim Yildirim, Nicolas Gomez, Genesis Rodriguez, Jaclyn Pak, Xingli Li, Christopher Altheim, Jacob Waksmacki, Gerald M McInerney, Sami J Barmada, Peter K Todd, Stress granule formation helps to mitigate neurodegeneration, Nucleic Acids Research, 2024;, gkae655, https://doi.org/10.1093/nar/gkae655
Supplementary data
Copyright
The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Animal Experimentation and Research Commons, Genetics Commons, Nervous System Diseases Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons
Comments
This article was originally published in Nucleic Acids Research in 2024. https://doi.org/10.1093/nar/gkae655