Relation Between Stress Granules and Cytoplasmic Protein Aggregates Linked to Neurodegenerative Diseases
A hallmark of neurodegenerative diseases is the accumulation of cytoplasmic protein aggregates in neurons of affected subjects. Among recently identified elements of these aggregates are RNA-binding proteins (RBPs) involved in RNA metabolism and alternative splicing and have in common the presence of low complexity domains (LCD) that are prone to self-assemble and form aggregates. The mechanism of cytoplasmic protein aggregation remains elusive. Stress granules (SGs) that are micrometric RNA-protein assemblies located in the cytoplasm of cells exposed to environmental stress are suspected to play the role of seeds. The review sheds light on the recent experimental results that suggest a link between SGs and cytoplasmic protein aggregates but also propose other routes for the formation of these aggregates.
Purpose of Review
To analyze the potential relationship between cytoplasmic protein aggregates in neurons of affected subjects and stress granules.
Liquid phase separation explains how protein and RNA could assemble in membraneless compartments, notably SGs. These results highlight the importance of RBPs with LCD in the SG assembly. Maturation of SGs and in particular the dense core is a potential source of insoluble protein aggregates.
Several lines of evidence linked stress granule dynamics to pathogenic protein aggregates. (i) Proteins that accumulate in cytoplasmic aggregates are also SG components. (ii) Neurons are specifically exposed to stress events due to their high metabolism and long lifespan. (iii) Diseases linked protein mutations affect the SG dynamics. (iv) SG dense core could be a breeding ground for protein aggregates. However, we should also keep in mind that SGs are not the only RNA-protein assembly in the cytoplasm; the RNA transport granules could also play a role in the formation of insoluble protein aggregates.
KeywordsRNA-binding protein Stress granules Low complexity domain Liquid-liquid phase separation Compartmentalization Neurodegenerative disease
Compliance with Ethical Standards
Conflict of Interest
Loic Hamon reports non-financial support from Genopole Evry, during the conduct of the study. Serhii Pankivskyi reports grants from Eiffel program, during the conduct of the study. Anastasiia Samsonova reports grants from MSD France, during the conduct of the study. Ioana Dobra and David Pastre each declare no potential conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 28.Maurel C, Madji-Hounoum B, Thepault RA, Marouillat S, Brulard C, Danel-Brunaud V, et al. Mutation in the RRM2 domain of TDP-43 in amyotrophic lateral sclerosis with rapid progression associated with ubiquitin positive aggregates in cultured motor neurons. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19:149–51.CrossRefGoogle Scholar
- 31.Paul KR, Molliex A, Cascarina S, Boncella AE, Taylor JP, Ross ED. Effects of mutations on the aggregation propensity of the human prion-like protein hnRNPA2B1. Mol Cell Biol. 2017;37.Google Scholar
- 46.St George-Hyslop P, Lin JQ, Miyashita A, Phillips EC, Qamar S, Randle SJ, et al. The physiological and pathological biophysics of phase separation and gelation of RNA binding proteins in amyotrophic lateral sclerosis and fronto-temporal lobar degeneration. Brain Res. 2018;1693:11–23.CrossRefGoogle Scholar
- 52.•• Van Treeck B, Parker R. Emerging roles for intermolecular RNA-RNA interactions in RNP assemblies. Cell. 2018;174:791–802. RNA-protein interactions are not alone to drive the assembly of SGs and other RNA-rich granules, we should also take into account the interactions between RNA molecules.CrossRefGoogle Scholar
- 53.Mittag T, Parker R. Multiple modes of protein-protein interactions promote RNP granule assembly. J Mol Biol. 2018.Google Scholar
- 58.•• Wheeler JR, Matheny T, Jain S, Abrisch R, Parker R. Distinct stages in stress granule assembly and disassembly. eLife. 2016;5. SGs are not homogeneous granules, they may display a dense core which could favor protein aggregation and a diffuse shel. Google Scholar
- 60.Daigle JG, Lanson NA Jr, Smith RB, Casci I, Maltare A, Monaghan J, et al. RNA-binding ability of FUS regulates neurodegeneration, cytoplasmic mislocalization and incorporation into stress granules associated with FUS carrying ALS-linked mutations. Hum Mol Genet. 2013;22:1193–205.CrossRefGoogle Scholar
- 66.Corcia P, Danel V, Lacour A, Beltran S, Andres C, Couratier P, et al. A novel mutation of the C-terminal amino acid of FUS (Y526C) strengthens FUS gene as the most frequent genetic factor in aggressive juvenile ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18:298–301.CrossRefGoogle Scholar
- 67.•• Monahan Z, Ryan VH, Janke AM, Burke KA, Rhoads SN, Zerze GH, et al. Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J. 2017;36:2951–67. Post-translational Modifications are also involved in protein phase separation. CrossRefGoogle Scholar