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

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.

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Publication Details

Journal
Molecular Neurodegeneration
Published
2025-03-28
DOI
https://doi.org/10.1186/s13024-025-00826-z
Citations
9
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
7.25

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article

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

Meghan M. Heer, Veronica S. Grybas, Maxime W.C. Rousseaux, Paul M. McKeever et al.
9 citations
Molecular Neurodegeneration
Ubiquitin and proteasome pathways
7.25
article

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

Meghan M. Heer, Veronica S. Grybas, Maxime W.C. Rousseaux, Paul M. McKeever, Benjamin Nguyen, Terry R. Suk, Jenny L. Zhang, Trina T. Nguyen, Steve Callaghan, Janice Robertson, John Woulfe, Caroline E. Part, Alejandro Caballero-Gómez, Tahir Ali
article en
9 citations

Abstract

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.

Molecular NeurodegenerationVol. 20(1)
University of Ottawa (CA), University of Toronto (CA), Ottawa Hospital (CA), MIND Research Institute (US), Occupational Cancer Research Centre (CA), uOttawa Brain and Mind Research Institute, Ottawa Institute of Systems Biology
ALS Society of Canada, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada
Good health and well-being
Openalex Percentile: Top 3%
Ubiquitin and proteasome pathways
7.25
DOIOpen Access PDFOpenAlex
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