Stress granules as crucibles of ALS pathogenesis

By Y. Li, Oliver D. King, J. Shorter, Aaron Gitler. Journal of Cell Biology, 2013

893 citations recorded by the source corpus.

Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.

Subfields: Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/fc17c028a805770c7ca9d89c3e0e543118e5ddb3

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Citations in the corpus

Hexanediol: a chemical probe to investigate the material properties of membrane-less compartments (2017, background): “The protein also relocates to stress granules upon environmental perturbations [4].”
Liquid-liquid phase separation in biology. (2014, background): “In other words, the original compartments form by liquid-liquid demixing, and the disease state could form by a liquid-solid phase transition (see Hyman & Brangwynne 2011, Li et al. 2013, Malinovska et al. 2013, Shulman et al. 2011, Weber & Brangwynne 2012 for further discussions).”
Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, positive): “A tempting speculation is that the association of TDP-43 and FUS/TLS with stress granules may be an initiating event, which following chronic stress eventually leads to irreversible pathological aggregation (Dormann et al., 2010; Dewey et al., 2012; Li et al., 2013).”
A census of human RNA-binding proteins (2014, background): “of these RNA-protein granules leads to cellular stress predominantly affecting neuronal cells (Buchan et al., 2013; Li et al., 2013; Liu-Yesucevitz et al., 2011; Ramaswami et al., 2013).”
Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity (2017, neutral): “…hypothesis is that RNA-binding protein aggregation in neurodegenerative diseases is seeded from cytoplasmic ribonucle-oprotein (RNP) granules (Li et al , 2013), including stress granules (SGs), processing bodies (P-bodies), and transport granules (Kiebler & Bassell, 2006; Thomas et al ,…”
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. (2015, neutral): “The Prion-like Protein FUS Assembles into Various Dynamic Compartments In Vivo Previous reports have implicated FUS in the formation of stressinducible compartments, such as DNA damage sites and stress granules (Li et al., 2013; Mastrocola et al., 2013; Rulten et al., 2014; Wang et al., 2013).”
Distinct stages in stress granule assembly and disassembly (2016, background): “Abnormal accumulation of stress granule-like aggregates is associated with neurodegenerative disease (Li et al., 2013; Ramaswami et al., 2013).”
ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function (2015, background): “Recently, attention has refocused on the possibility that mutant ALS/FTD-associated RBPs might be incorporated into and alter the function of ribonucleoprotein (RNP) granules (Li et al., 2013; Mitchell and Parker, 2014; Ramaswami et al., 2013; Wolozin, 2012).”
The stress granule transcriptome reveals principles of mRNA accumulation in stress granules (2017, neutral): “SGs also share many protein components with neuronal granules, and mutations that increase SG formation or perturb SG clearance are implicated in degenerative diseases such as amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy, where aberrant SG-like assemblies form (Buchan et al., 20”
Principles and Properties of Stress granules (2016, background): “Third, mutations that increase stress granule formation and/or limit stress granule clearance are causative in some neurodegenerative diseases [15,16].”
Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization (2015, neutral): “A wealth of genetic evidence has emerged over the past 5 years implicating stress granules as a subcellular compartment that is central to the pathogenesis of a closely related set of degenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and inclusion b”