Stress granules (SGs) are cytoplasmic membraneless organelles that form through [liquid-liquid phase separation](/mechanisms/liquid-liquid-phase-separation) when cells encounter stress conditions such as oxidative stress, heat shock, viral infection, or proteotoxic stress. In the context of neurodegeneration, stress granule dynamics — their assembly, composition, and critically their disassembly — have emerged as a central pathological mechanism linking [TDP-43](/proteins/tdp-43-protein), [FUS](/genes/fus), and other RNA-binding proteins to [ALS](/diseases/amyotrophic-lateral-sclerosis), [FTD](/diseases/behavioral-variant-ftd), and related proteinopathies.
Under normal conditions, stress granules are transient structures that sequester mRNAs and translation machinery to prioritize survival-related gene expression. When stress resolves, SGs disassemble rapidly. In neurodegenerative diseases, mutations in SG-resident proteins impair disassembly, leading to persistent SGs that mature into pathological aggregates. This "stress granule hypothesis" has become a unifying framework for understanding how RNA-binding protein dysfunction drives neurodegeneration. [@patel2015]
Stress Granule Composition
Core Components
Stress granules contain a dense protein-RNA network organized around stalled translation pre-initiation complexes: [@mackenzie2017]
...
Stress Granule Dynamics in Neurodegeneration
Overview
Stress granules (SGs) are cytoplasmic membraneless organelles that form through [liquid-liquid phase separation](/mechanisms/liquid-liquid-phase-separation) when cells encounter stress conditions such as oxidative stress, heat shock, viral infection, or proteotoxic stress. In the context of neurodegeneration, stress granule dynamics — their assembly, composition, and critically their disassembly — have emerged as a central pathological mechanism linking [TDP-43](/proteins/tdp-43-protein), [FUS](/genes/fus), and other RNA-binding proteins to [ALS](/diseases/amyotrophic-lateral-sclerosis), [FTD](/diseases/behavioral-variant-ftd), and related proteinopathies.
Under normal conditions, stress granules are transient structures that sequester mRNAs and translation machinery to prioritize survival-related gene expression. When stress resolves, SGs disassemble rapidly. In neurodegenerative diseases, mutations in SG-resident proteins impair disassembly, leading to persistent SGs that mature into pathological aggregates. This "stress granule hypothesis" has become a unifying framework for understanding how RNA-binding protein dysfunction drives neurodegeneration. [@patel2015]
Stress Granule Composition
Core Components
Stress granules contain a dense protein-RNA network organized around stalled translation pre-initiation complexes: [@mackenzie2017]
RNA-binding proteins (RBPs): [@becker2017]
[TDP-43](/proteins/tdp-43-protein): Major SG component, shuttles between nucleus and cytoplasm; its cytoplasmic mislocalization is the hallmark of ALS/FTD pathology
[FUS](/genes/fus): RNA-binding protein that phase separates into SGs; mutations cause [ALS-FUS](/mechanisms/als-fus-pathway) and [FTD-FUS](/mechanisms/ftd-fus-pathway)
G3BP1/G3BP2: Core nucleating factors essential for SG assembly; their dimerization initiates SG condensation
TIA-1/TIAR: RNA-binding proteins with prion-like domains that scaffold SG assembly
[hnRNPA1](/genes/hnrnpa1): Heterogeneous nuclear ribonucleoprotein A1; mutations cause multisystem proteinopathy
[hnRNPA2B1](/genes/hnrnpa2b1): Related hnRNP family member also linked to degenerative disease
ATXN2 ([Ataxin-2](/genes/atxn2)): Polyglutamine protein; intermediate-length expansions are a risk factor for [ALS](/diseases/amyotrophic-lateral-sclerosis)
Translation machinery: [@molliex2015]
40S ribosomal subunits (but NOT 60S subunits or polysomes)
Maturation: Liquid droplets recruit additional components and develop internal organization
Disassembly Pathway
Normal SG disassembly requires: [@guillnboixet2020]
VCP/p97 (Valosin-containing protein): AAA+ ATPase that extracts ubiquitinated proteins from SGs; mutations in [VCP](/genes/vcp) cause multisystem proteinopathy with ALS/FTD features
Chaperones: [HSP70](/proteins/hsp70-protein)/HSP40 systems prevent irreversible aggregation within SGs
Autophagy: [Selective autophagy (granulophagy)](/mechanisms/autophagy-lysosomal-pathway) clears SGs via the receptor SQSTM1/p62
ZFAND1: Zinc finger protein that recruits the 26S proteasome and VCP/p97 to SGs
Dephosphorylation: eIF2α dephosphorylation by GADD34/PP1 restores translation
Pathological Mechanisms in Neurodegeneration
TDP-43 and Stress Granules
[TDP-43](/proteins/tdp-43-protein) proteinopathy is the pathological hallmark of ~97% of [ALS](/diseases/amyotrophic-lateral-sclerosis) cases and ~45% of [FTD](/diseases/behavioral-variant-ftd) cases: [@zhang2019]
Nuclear depletion: TDP-43 normally resides in the nucleus where it regulates RNA splicing. In disease, it mislocalizes to the cytoplasm
SG recruitment: Cytoplasmic TDP-43 is recruited to stress granules through its C-terminal prion-like domain (glycine-rich domain)
Impaired disassembly: ALS-linked TDP-43 mutations (A315T, M337V, Q331K, G348C) enhance its propensity for irreversible aggregation within SGs
Pathological maturation: Persistent TDP-43-containing SGs undergo liquid-to-solid phase transition, forming the ubiquitinated, hyperphosphorylated, C-terminally cleaved TDP-43 inclusions seen in patient tissue
Loss of function: Nuclear TDP-43 depletion leads to aberrant [RNA splicing](/mechanisms/rna-splicing-defects), including [cryptic exon inclusion](/mechanisms/cryptic-exon-splicing), which contributes to neuronal dysfunction
FUS and Stress Granules
[FUS](/genes/fus) mutations cause a subset of [ALS](/diseases/amyotrophic-lateral-sclerosis) and rare [FTD](/diseases/behavioral-variant-ftd) cases: [@gassetrosa2019]
FUS contains a low-complexity prion-like domain (LCD) at its N-terminus that drives phase separation
ALS mutations cluster in the nuclear localization signal (NLS), causing cytoplasmic FUS mislocalization
Cytoplasmic FUS is incorporated into SGs with accelerated liquid-to-solid transition
FUS mutations (P525L, R521C, R521G) show graded severity correlating with degree of cytoplasmic mislocalization
Juvenile ALS cases with FUS-P525L show the most severe SG accumulation
G3BP1 as a Therapeutic Target
G3BP1 is the primary SG nucleation factor and a potential therapeutic target: [@yang2020]
G3BP1 knockout prevents SG formation and may reduce pathological aggregation
Small molecules disrupting G3BP1 dimerization could limit SG nucleation
However, SG formation also serves protective functions — complete inhibition may be harmful
The challenge is to modulate SG dynamics without eliminating their physiological role
Ataxin-2 and SG Dynamics
[Ataxin-2](/genes/atxn2) intermediate-length polyglutamine expansions (27-33 CAQs) are a genetic risk factor for [ALS](/diseases/amyotrophic-lateral-sclerosis):
Ataxin-2 is a core SG component that promotes SG assembly
Intermediate expansions enhance Ataxin-2's role in SG nucleation
Ataxin-2 interacts directly with TDP-43 in SGs
Reducing Ataxin-2 levels with antisense oligonucleotides (ASOs) extends survival in TDP-43 mouse models
The Ataxin-2 ASO (BIIB105/ION541) entered clinical trials for ALS
Liquid-to-Solid Phase Transition
The conversion from dynamic liquid droplets to solid, fibrillar aggregates is a key pathological event:
Mermaid diagram (expand to render)
Factors promoting pathological phase transition:
Mutations in prion-like domains: ALS/FTD mutations in [TDP-43](/mechanisms/tdp-43-proteinopathy), FUS, hnRNPA1, hnRNPA2B1 accelerate fibrillization
Post-translational modifications: Hyperphosphorylation, ubiquitination, acetylation, and methylation alter phase separation behavior
Concentration: Higher local protein concentrations drive gelation
RNA depletion: Reduced RNA:protein ratios in SGs promote solid transitions (RNA acts as a buffer against aggregation)
Aging: Age-related decline in protein quality control allows longer SG persistence
Repeat stress: Repeated cycles of SG assembly and disassembly lead to cumulative aggregation
Connections to Other Mechanisms
Autophagy and Granulophagy
[Autophagy](/mechanisms/autophagy-lysosomal-pathway) selectively clears stress granules through a process called granulophagy:
SQSTM1/p62 recognizes ubiquitinated SG components
[VCP/p97](/genes/vcp) extracts ubiquitinated proteins for proteasomal degradation
Impaired [autophagy-lysosomal function](/mechanisms/autophagy-lysosome-pathway) leads to SG accumulation
[C9orf72](/genes/c9orf72) protein itself regulates [autophagy](/entities/autophagy); its loss impairs SG clearance
[G et al. 2025: Dissecting the stress granule RNA world: dynamics, strategies, and dat](https://pubmed.ncbi.nlm.nih.gov/40086831/)
[Y et al. 2025: Proteotoxic stress response drives T cell exhaustion and immune evasio](https://pubmed.ncbi.nlm.nih.gov/41034580/)
[F et al. 2025: RIOK1 phase separation restricts PTEN translation via stress granules ](https://pubmed.ncbi.nlm.nih.gov/40467995/)
[MR et al. 2024: Stress granule formation helps to mitigate neurodegeneration.](https://pubmed.ncbi.nlm.nih.gov/39106168/)
[P et al. 2024: NS1 binding protein regulates stress granule dynamics and clearance by](https://pubmed.ncbi.nlm.nih.gov/39738171/)
References
[Unknown, Wolozin & Ivanov, Stress Granules and Neurodegeneration (2019) (2019)](https://doi.org/10.1038/s41583-019-0222-5)
[Patel et al., A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation (2015) (2015)](https://doi.org/10.1016/j.cell.2015.07.047)
[Mackenzie et al., TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics (2017) (2017)](https://doi.org/10.1016/j.neuron.2017.07.025)
[Becker et al., Therapeutic Reduction of Ataxin-2 Extends Lifespan and Reduces Pathology in TDP-43 Mice (2017) (2017)](https://doi.org/10.1038/nature23494)
[Molliex et al., Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization (2015) (2015)](https://doi.org/10.1016/j.cell.2015.09.015)
[Wheeler et al., Distinct Stages in Stress Granule Assembly and Disassembly (2016) (2016)](https://doi.org/10.7554/eLife.18413)
[Guillén-Boixet et al., RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation (2020) (2020)](https://doi.org/10.1016/j.cell.2020.03.049)
[Zhang et al., Chronic Optogenetic Induction of Stress Granules Is Cytotoxic and Reveals the Evolution of ALS-FTD Pathology (2019) (2019)](https://doi.org/10.7554/eLife.39578)
[Gasset-Rosa et al., Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death (2019) (2019)](https://doi.org/10.1016/j.neuron.2019.02.038)
[Yang et al., G3BP1 Is a Tunable Switch that Triggers Phase Separation to Assemble Stress Granules (2020) (2020)](https://doi.org/10.1016/j.cell.2020.03.046)