TDP-43 is recruited to stress granules in conditions of oxidative insult

Topic: Brain proteins, microglia and lab models

Transactive response DNA-binding protein 43 (TDP-43) forms abnormal ubiquitinated and phosphorylated inclusions in brain tissues from patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. TDP-43 is a DNA/RNA-binding protein involved in RNA processing, such as transcription, pre-mRNA splicing, mRNA stabilization and transport to dendrites. We found that in response to oxidative stress and to environmental insults of different types TDP-43 is capable to assemble into stress granules (SGs), ribonucleoprotein complexes where protein synthesis is temporarily arrested. We demonstrated that a specific aminoacidic interval (216-315) in the C-terminal region and the RNA-recognition motif 1 domain are both implicated in TDP-43 participation in SGs as their deletion prevented the recruitment of TDP-43 into SGs. Our data show that TDP-43 is a specific component of SGs and not of processing bodies, although we proved that TDP-43 is not necessary for SG formation, and its gene silencing does not impair cell survival during stress. The analysis of spinal cord tissue from ALS patients showed that SG markers are not entrapped in TDP-43 pathological inclusions. Although SGs were not evident in ALS brains, we speculate that an altered control of mRNA translation in stressful conditions may trigger motor neuron degeneration at early stages of the disease.

Key findings

• We found that in response to oxidative stress and to environmental insults of different types TDP-43 is capable to assemble into stress granules (SGs), ribonucleoprotein complexes where protein synthesis is temporarily arrested.
• We demonstrated that a specific aminoacidic interval (216-315) in the C-terminal region and the RNA-recognition motif 1 domain are both implicated in TDP-43 participation in SGs as their deletion prevented the recruitment of TDP-43 into SGs.
• The analysis of spinal cord tissue from ALS patients showed that SG markers are not entrapped in TDP-43 pathological inclusions.

Why it matters

In laboratory work, TDP-43 assembled into stress granules under oxidative stress, and specific parts of the protein were needed for this, though stress granule markers were not found inside TDP-43 inclusions in ALS spinal cord. This is early cell and tissue work on a possible early disease mechanism, not a treatment.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1111/j.1471-4159.2009.06383.x
• PubMed: 19765185
• Original source →

May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.

@article{colombrita2009-19765185,
  author  = {Colombrita, C. and Zennaro, E. and Fallini, C. and Weber, M. and Sommacal, A. and Buratti, E. and Silani, V. and Ratti, A.},
  title   = {{TDP-43 is recruited to stress granules in conditions of oxidative insult}},
  journal = {Journal of neurochemistry},
  year    = {2009},
  doi     = {10.1111/j.1471-4159.2009.06383.x},
  pmid    = {19765185},
  url     = {https://doi.org/10.1111/j.1471-4159.2009.06383.x}
}

Studies this one cites

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• 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
• Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases Acta neuropathologica · 2007-07-25 · usefulness score 59/100 · How common it is
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease Annals of neurology · 2007-05-01 · usefulness score 56/100 · 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
• Structural determinants of the cellular localization and shuttling of TDP-43 Journal of cell science · 2008-10-28 · usefulness score 51/100 · Lewy body dementia
• Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease Journal of neuropathology and experimental neurology · 2008-12-01 · usefulness score 45/100 · Brain tissue and pathology

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• Structure of pathological TDP-43 filaments from ALS with FTLD Nature · 2021-12-08 · usefulness score 58/100 · Lewy body dementia
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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
• 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
• Stress granules and neurodegeneration Nature reviews. Neuroscience · 2019-10-03 · 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
• 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
• An acetylation switch controls TDP-43 function and aggregation propensity Nature communications · 2015-01-05 · usefulness score 54/100 · Lewy body dementia

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