A stress-dependent TDP-43 SUMOylation program preserves neuronal function

Topic: Brain proteins, microglia and lab models

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors - such as cellular stressors - converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such exogenous stressors. We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease. We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors. When this process is blocked in vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease. We further find that SUMOylation is correlated with human aging and disease states. Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.

Key findings

• We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease.
• We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors.
• When this process is blocked in vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease.
• We further find that SUMOylation is correlated with human aging and disease states.
• Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.

Why it matters

In animal work, blocking TDP-43 SUMOylation led to age-dependent TDP-43 pathology and sex-specific behavioral deficits, and SUMOylation was correlated with human aging and disease states. This presents SUMOylation as an early physiological stress response whose disruption may raise risk, but no treatment is tested in patients.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/s13024-025-00826-z
• PubMed: 40149017
• Original source →
• Free full text: Molecular Neurodegeneration →

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

@article{suk2025-40149017,
  author  = {Suk, Terry R. and Part, Caroline E. and Zhang, Jenny L. and Nguyen, Trina T. and Heer, Meghan M. and Caballero-Gómez, Alejandro and Grybas, Veronica S. and McKeever, Paul M. and others},
  title   = {{A stress-dependent TDP-43 SUMOylation program preserves neuronal function}},
  journal = {Molecular Neurodegeneration},
  year    = {2025},
  doi     = {10.1186/s13024-025-00826-z},
  pmid    = {40149017},
  url     = {https://doi.org/10.1186/s13024-025-00826-z}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 20.

• Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report Brain : a journal of neurology · 2019-06-01 · usefulness score 67/100 · Prevention and risk
• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration Nature neuroscience · 2019-01-14 · usefulness score 62/100 · 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
• 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
• The frontotemporal dementia-motor neuron disease continuum Lancet (London, England) · 2016-03-14 · usefulness score 56/100 · Getting a diagnosis
• Interactions of pathological proteins in neurodegenerative diseases Acta neuropathologica · 2017-04-11 · usefulness score 56/100 · Lewy body dementia
• TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD Nature neuroscience · 2018-03-19 · usefulness score 56/100 · Brain tissue and pathology
• 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 Pathology in Alzheimer's Disease Molecular neurodegeneration · 2021-12-20 · 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

Later studies that cite this one

3 studies in the alzhub library list this one in their references.

• Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses Cells · 2025-05-08 · usefulness score 44/100 · Brain tissue and pathology
• TDP-43: [GU]-ardian of the transcriptome Molecular Neurodegeneration · 2026-05-14 · usefulness score 42/100 · Brain tissue and pathology
• From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis International Journal of Molecular Sciences · 2026-01-23 · usefulness score 36/100 · Brain tissue and pathology

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