Stress granule formation helps to mitigate neurodegeneration

Nucleic Acids Res. 2024 Sep 9;52(16):9745-9759. doi: 10.1093/nar/gkae655.

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.

MeSH terms

  • Alphavirus / genetics
  • Alphavirus / metabolism
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Animals
  • Ataxia / genetics
  • Ataxia / metabolism
  • Carrier Proteins / metabolism
  • Cytoplasmic Granules / metabolism
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA-Binding Proteins
  • Drosophila / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Frontotemporal Dementia* / genetics
  • Frontotemporal Dementia* / metabolism
  • Humans
  • Mice
  • Neurodegenerative Diseases* / genetics
  • Neurodegenerative Diseases* / metabolism
  • Neurons* / metabolism
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • RNA Helicases / genetics
  • RNA Helicases / metabolism
  • RNA Recognition Motif Proteins / genetics
  • RNA Recognition Motif Proteins / metabolism
  • Rats
  • Stress Granules* / metabolism
  • Stress, Physiological

Substances

  • RNA Recognition Motif Proteins
  • Drosophila Proteins
  • Poly-ADP-Ribose Binding Proteins
  • RNA Helicases
  • DNA Helicases
  • TBPH protein, Drosophila
  • Carrier Proteins
  • G3BP1 protein, human
  • DNA-Binding Proteins