Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43Q331K mice
6 affiliations
- 1Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA
- 2NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA
- 3Department of Ophthalmology, University of Missouri-Columbia, Columbia, MO, USA
- 4Department of Genetics, Harvard Medical School, Boston, MA, USA
- 5Department of Physiology and Biomedical Engineering, Robert & Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
- 6The Sam and Ann Barshop Institute for Longevity and Aging Studies; Department of Cellular and Integrative Physiology, UT Health San Antonio, San Antonio, TX, USA
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration in the motor cortex and spinal cord. Aging is a key risk factor for ALS, and cellular senescence – a hallmark of aging marked by irreversible cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype – has been implicated in neurodegeneration, yet its role in ALS progression remains incompletely understood. Here, we show that molecular markers of cellular senescence emerge in the motor cortex and spinal cord alongside declines in neural and neuromuscular function in TDP-43Q331K ALS mice, supporting senescence as an early feature of ALS pathology. To test whether reduced senescence ameliorates ALS pathology, we evaluated longitudinal senolytic treatment with dasatinib and quercetin (D&Q) in TDP-43Q331K mice. D&Q treatment improved motor behavior, neuromuscular function, and reduced axonal damage as measured by plasma neurofilament light chain, accompanied by robust improvements in motor cortex excitability and preservation of layer V neuron counts. At the cellular level, cortical microglia were implicated as a potential mediator of senolytic benefits based on reduced microglial TDP-43 burden and senescence markers. Together, these findings identify cellular senescence as an early, disease-relevant, and modifiable feature of ALS pathology.
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BibTeX
@article{viteri2026cellular,
title = {{Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43Q331K mice}},
author = {Jose A. Viteri and Nathan R. Kerr and Charles D. Brennan and Grace R. Kick and Meifang Wang and Arsh Ketabforoush and Harper J. Snyder and Peter J. Moore and Fereshteh B. Darvishi and Anna R. Dashtmian and Sindhuja N. Ayyagari and Kelly Rich and Yi Zhu and Hiroshi Nishimune and W. David Arnold},
journal = {Neurobiology of disease},
year = {2026},
month = sep,
doi = {10.1016/j.nbd.2026.107610},
url = {https://doi.org/10.1016/j.nbd.2026.107610},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43Q331K mice
AU - Jose A. Viteri
AU - Nathan R. Kerr
AU - Charles D. Brennan
AU - Grace R. Kick
AU - Meifang Wang
AU - Arsh Ketabforoush
AU - Harper J. Snyder
AU - Peter J. Moore
AU - Fereshteh B. Darvishi
AU - Anna R. Dashtmian
AU - Sindhuja N. Ayyagari
AU - Kelly Rich
AU - Yi Zhu
AU - Hiroshi Nishimune
AU - W. David Arnold
PY - 2026
DA - 2026/09/18
JO - Neurobiology of disease
DO - 10.1016/j.nbd.2026.107610
UR - https://doi.org/10.1016/j.nbd.2026.107610
AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration in the motor cortex and spinal cord. Aging is a key risk factor for ALS, and cellular senescence – a hallmark of aging marked by irreversible cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype – has been implicated in neurodegeneration, yet its role in ALS progression remains incompletely understood. Here, we show that molecular markers of cellular senescence emerge in the motor cortex and spinal cord alongside declines in neural and neuromuscular function in TDP-43Q331K ALS mice, supporting senescence as an early feature of ALS pathology. To test whether reduced senescence ameliorates ALS pathology, we evaluated longitudinal senolytic treatment with dasatinib and quercetin (D&Q) in TDP-43Q331K mice. D&Q treatment improved motor behavior, neuromuscular function, and reduced axonal damage as measured by plasma neurofilament light chain, accompanied by robust improvements in motor cortex excitability and preservation of layer V neuron counts. At the cellular level, cortical microglia were implicated as a potential mediator of senolytic benefits based on reduced microglial TDP-43 burden and senescence markers. Together, these findings identify cellular senescence as an early, disease-relevant, and modifiable feature of ALS pathology.
SN - 0969-9961
SN - 1095-953X
ER -