Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization

Topic: Brain proteins, microglia and lab models

In amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), cytoplasmic aggregates of hyperphosphorylated TDP-43 accumulate and colocalize with some stress granule components, but how pathological TDP-43 aggregation is nucleated remains unknown. In Drosophila, we establish that downregulation of tankyrase, a poly(ADP-ribose) (PAR) polymerase, reduces TDP-43 accumulation in the cytoplasm and potently mitigates neurodegeneration. We establish that TDP-43 non-covalently binds to PAR via PAR-binding motifs embedded within its nuclear localization sequence. PAR binding promotes liquid-liquid phase separation of TDP-43 in vitro and is required for TDP-43 accumulation in stress granules in mammalian cells and neurons. Stress granule localization initially protects TDP-43 from disease-associated phosphorylation, but upon long-term stress, stress granules resolve, leaving behind aggregates of phosphorylated TDP-43. Finally, small-molecule inhibition of Tankyrase-1/2 in mammalian cells inhibits formation of cytoplasmic TDP-43 foci without affecting stress granule assembly. Thus, Tankyrase inhibition antagonizes TDP-43-associated pathology and neurodegeneration and could have therapeutic utility for ALS and FTD.

Key findings

• We establish that TDP-43 non-covalently binds to PAR via PAR-binding motifs embedded within its nuclear localization sequence.
• PAR binding promotes liquid-liquid phase separation of TDP-43 in vitro and is required for TDP-43 accumulation in stress granules in mammalian cells and neurons.
• Stress granule localization initially protects TDP-43 from disease-associated phosphorylation, but upon long-term stress, stress granules resolve, leaving behind aggregates of phosphorylated TDP-43.
• Finally, small-molecule inhibition of Tankyrase-1/2 in mammalian cells inhibits formation of cytoplasmic TDP-43 foci without affecting stress granule assembly.
• Thus, Tankyrase inhibition antagonizes TDP-43-associated pathology and neurodegeneration and could have therapeutic utility for ALS and FTD.

Why it matters

In fruit flies, turning down the enzyme tankyrase reduced TDP-43, a protein that clumps in ALS and frontotemporal dementia, building up outside the cell nucleus and "potently mitigates neurodegeneration". In lab and cell experiments, the molecule tankyrase makes (poly(ADP-ribose)) drew TDP-43 into stress granules, which "initially protects" it, but under long-term stress those granules resolve, "leaving behind aggregates of phosphorylated TDP-43". A tankyrase-blocking compound reduced TDP-43 clumps in mammalian cells; the authors say this "could have therapeutic utility for ALS and FTD", but it was not tested in people and the study does not address Alzheimer's.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.molcel.2018.07.002
• PubMed: 30100264
• Original source →
• Free full text: Molecular Cell →

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

@article{mcgurk2018-30100264,
  author  = {McGurk, L. and Gomes, E. and Guo, L. and Mojsilovic-Petrovic, J. and Tran, V. and Kalb, R. G. and Shorter, J. and Bonini, N. M.},
  title   = {{Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization}},
  journal = {Molecular cell},
  year    = {2018},
  doi     = {10.1016/j.molcel.2018.07.002},
  pmid    = {30100264},
  url     = {https://doi.org/10.1016/j.molcel.2018.07.002}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 17.

• Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations Annals of neurology · 2007-05-01 · usefulness score 63/100 · Brain tissue and pathology
• 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
• Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice Nature · 2017-04-12 · usefulness score 61/100 · Lewy body dementia
• TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics Neuron · 2017-08-01 · usefulness score 58/100 · Caregiving
• Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization Cell · 2015-09-01 · usefulness score 56/100 · Lewy body dementia
• Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue PloS one · 2010-10-11 · usefulness score 55/100 · Lewy body dementia
• Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation Nature communications · 2017-06-29 · usefulness score 55/100 · Lewy body dementia
• Stress Granule Assembly Disrupts Nucleocytoplasmic Transport Cell · 2018-04-05 · usefulness score 55/100 · Lewy body dementia
• Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Annals of neurology · 2008-07-01 · usefulness score 54/100 · Lewy body dementia
• Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation The Journal of biological chemistry · 2008-02-27 · usefulness score 53/100 · 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
• Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS PLoS biology · 2011-04-26 · usefulness score 52/100 · Lewy body dementia

Later studies that cite this one

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• 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
• Stress granules and neurodegeneration Nature reviews. Neuroscience · 2019-10-03 · usefulness score 55/100 · Lewy body dementia
• TDP-43 proteinopathies: a new wave of neurodegenerative diseases Journal of neurology, neurosurgery, and psychiatry · 2020-11-11 · usefulness score 54/100 · Lewy body dementia
• RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43 Neuron · 2019-02-27 · usefulness score 53/100 · Lewy body dementia
• SUMO2/3 conjugation of TDP-43 protects against aggregation Science Advances · 2025-02-21 · usefulness score 52/100 · Brain tissue and pathology
• Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD Neuron · 2019-07-01 · usefulness score 52/100 · Brain tissue and pathology
• The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain The Journal of biological chemistry · 2019-02-27 · usefulness score 50/100 · Lewy body dementia
• Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis Frontiers in molecular neuroscience · 2019-02-14 · usefulness score 50/100 · Lewy body dementia

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• FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions Cell · 2018-04-01 · usefulness score 59/100
• Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity The EMBO journal · 2017-08-08 · usefulness score 57/100
• Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation Cell · 2018-04-01 · usefulness score 54/100
• Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation Molecular cell · 2018-01-18 · usefulness score 50/100
• Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner Science (New York, N.Y.) · 2021-06-01 · usefulness score 55/100
• The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity Nature medicine · 2016-06-27 · usefulness score 58/100

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