Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS

Topic: Brain proteins, microglia and lab models

TDP-43 and FUS are RNA-binding proteins that form cytoplasmic inclusions in some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Moreover, mutations in TDP-43 and FUS are linked to ALS and FTLD. However, it is unknown whether TDP-43 and FUS aggregate and cause toxicity by similar mechanisms. Here, we exploit a yeast model and purified FUS to elucidate mechanisms of FUS aggregation and toxicity. Like TDP-43, FUS must aggregate in the cytoplasm and bind RNA to confer toxicity in yeast. These cytoplasmic FUS aggregates partition to stress granule compartments just as they do in ALS patients. Importantly, in isolation, FUS spontaneously forms pore-like oligomers and filamentous structures reminiscent of FUS inclusions in ALS patients. FUS aggregation and toxicity requires a prion-like domain, but unlike TDP-43, additional determinants within a RGG domain are critical for FUS aggregation and toxicity. In further distinction to TDP-43, ALS-linked FUS mutations do not promote aggregation. Finally, genome-wide screens uncovered stress granule assembly and RNA metabolism genes that modify FUS toxicity but not TDP-43 toxicity. Our findings suggest that TDP-43 and FUS, though similar RNA-binding proteins, aggregate and confer disease phenotypes via distinct mechanisms. These differences will likely have important therapeutic implications.

Key findings

• Our findings suggest that TDP-43 and FUS, though similar RNA-binding proteins, aggregate and confer disease phenotypes via distinct mechanisms.

Why it matters

Using a yeast model and purified FUS, this study found that FUS aggregation and toxicity require a prion-like domain and RGG domain determinants, and that ALS-linked FUS mutations do not promote aggregation. It suggests TDP-43 and FUS cause disease by distinct mechanisms, which may affect treatment design, but it is laboratory work.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1371/journal.pbio.1000614
• PubMed: 21541367
• Original source →
• Free full text: PLoS Biology →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{sun2011-21541367,
  author  = {Sun, Z. and Diaz, Z. and Fang, X. and Hart, M. P. and Chesi, A. and Shorter, J. and Gitler, A. D.},
  title   = {{Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS}},
  journal = {PLoS biology},
  year    = {2011},
  doi     = {10.1371/journal.pbio.1000614},
  pmid    = {21541367},
  url     = {https://doi.org/10.1371/journal.pbio.1000614}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 22.

• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis The Lancet. Neurology · 2008-04-07 · usefulness score 61/100 · Lewy body dementia
• Phenotype associated with APP duplication in five families Brain : a journal of neurology · 2006-09-07 · usefulness score 57/100 · Brain tissue and pathology
• TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia The Lancet. Neurology · 2010-10-01 · usefulness score 57/100 · Lewy body dementia
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia
• Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity Proceedings of the National Academy of Sciences of the United States of America · 2009-04-21 · usefulness score 55/100 · Lewy body dementia
• Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity Nature genetics · 2009-02-01 · usefulness score 54/100 · Risk factors
• TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration Annals of neurology · 2009-04-01 · usefulness score 54/100 · Brain tissue and pathology
• Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-01-01 · usefulness score 54/100 · Lewy body dementia
• TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity The Journal of biological chemistry · 2009-05-22 · usefulness score 53/100 · Lewy body dementia
• FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration Acta neuropathologica · 2010-05-20 · usefulness score 53/100 · Brain tissue and pathology

Later studies that cite this one

15 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS Nature neuroscience · 2015-09-01 · usefulness score 59/100 · Lewy body dementia
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity The EMBO journal · 2017-08-08 · usefulness score 57/100 · Lewy body dementia
• Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death Neuron · 2019-03-07 · usefulness score 56/100 · Lewy body dementia
• Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation Cell · 2018-04-01 · usefulness score 54/100 · Lewy body dementia
• Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization Molecular cell · 2018-08-09 · usefulness score 53/100 · Lewy body dementia
• The seeds of neurodegeneration: prion-like spreading in ALS Cell · 2011-10-01 · usefulness score 53/100 · Brain tissue and pathology
• The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease Brain research · 2012-01-21 · usefulness score 52/100 · Lewy body dementia

Related studies in Lewy body dementia

• Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs Nature neuroscience · 2012-09-30 · usefulness score 56/100
• Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation Nature communications · 2017-06-29 · usefulness score 55/100
• Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins Journal of neurochemistry · 2016-06-15 · usefulness score 49/100
• FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions Cell · 2018-04-01 · usefulness score 59/100
• The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity The Journal of neuroscience : the official journal of the Society for Neuroscience · 2000-08-01 · usefulness score 46/100
• RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention Neuron · 2013-10-01 · usefulness score 57/100

Also tagged “mice”

1,150 studies in the library carry the topic tag “mice”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation Nature medicine · 2005-03-20 · usefulness score 52/100 · Brain tissue and pathology
• Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis Journal of virology · 2018-07-31 · usefulness score 43/100 · TREM2 and immune genetics
• Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice Antioxidants & redox signaling · 2015-07-29 · usefulness score 40/100 · Inflammation and the immune system

Similar studies

• Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses 2025 · Brain tissue and pathology
• ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS 2018 · Disease mechanisms
• Understanding the role of TDP-43 and FUS/TLS in ALS and beyond 2011 · Brain tissue and pathology
• ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import 2010 · Lewy body dementia
• Loss of Dynamic RNA Interaction and Aberrant Phase Separation Induced by Two Distinct Types of ALS/FTD-Linked FUS Mutations 2020 · Clinical safety
• SnapShot: Genetics of ALS and FTD 2015 · Digital health tools

More on Lewy body dementia

• A review that covers this ground Molecular mechanisms underlying nucleotide repeat expansion disorders Nature reviews. Molecular cell biology · 2021-06-17 · usefulness score 53/100
• Newest in this subject Frequency-Resolved Connectivity Graphs for EEG-Based Classification of Alzheimer and Frontotemporal Dementia bioRxiv · 2026-10-22 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Dementia and PDE5 inhibitors: A retrospective cohort study of veterans Research Square · 2026-10-13 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Lewy body dementia →