Academic Journal
Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43Q331K mice.
| Τίτλος: | Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43Q331K mice. |
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| Συγγραφείς: | Viteri JA; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Kerr NR; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Brennan CD; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Kick GR; Department of Ophthalmology, University of Missouri-Columbia, Columbia, MO, USA., Wang M; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Ketabforoush A; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Snyder HJ; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Moore PJ; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Darvishi FB; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Dashtmian AR; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Ayyagari SN; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Rich K; Department of Genetics, Harvard Medical School, Boston, MA, USA., Zhu Y; Department of Physiology and Biomedical Engineering, Robert & Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; The Sam and Ann Barshop Institute for Longevity and Aging Studies; Department of Cellular and Integrative Physiology, UT Health San Antonio, San Antonio, TX, USA., Nishimune H; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA., Arnold WD; Department of Physical Medicine and Rehabilitation, University of Missouri-Columbia, Columbia, MO, USA; NextGen Precision Health, University of Missouri-Columbia, Columbia, MO, USA. Electronic address: wdavidarnold@health.missouri.edu. |
| Πηγή: | Neurobiology of disease [Neurobiol Dis] 2026 Oct 15; Vol. 229, pp. 107610. Date of Electronic Publication: 2026 Sep 18. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE |
| Imprint Name(s): | Publication: San Diego, CA : Academic Press Original Publication: Oxford : Blackwell Science, c1994- |
| Ιατρικοί όροι (MeSH): | Amyotrophic Lateral Sclerosis*/pathology , Amyotrophic Lateral Sclerosis*/genetics , Amyotrophic Lateral Sclerosis*/drug therapy , Amyotrophic Lateral Sclerosis*/metabolism , Amyotrophic Lateral Sclerosis*/physiopathology , DNA-Binding Proteins*/genetics , DNA-Binding Proteins*/metabolism , Cellular Senescence*/drug effects , Cellular Senescence*/physiology, Spinal Cord/pathology ; Spinal Cord/metabolism ; Spinal Cord/drug effects ; Dasatinib/pharmacology ; Senotherapeutics/pharmacology ; Motor Cortex/pathology ; Motor Cortex/drug effects ; Motor Cortex/metabolism ; Quercetin/pharmacology ; Motor Neurons/pathology ; Motor Neurons/drug effects ; Motor Neurons/metabolism ; Microglia/metabolism ; Microglia/pathology ; Microglia/drug effects ; Animals ; Mice ; Mice, Transgenic ; Disease Models, Animal |
| Περίληψη: | 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. (Copyright © 2026. Published by Elsevier Inc.) |
| Competing Interests: | Declaration of competing interest The authors declare no conflicts of interest. |
| Contributed Indexing: | Keywords: ALS; Aging; Motor cortex; Neuromuscular; Senescence; Senolytics |
| Substance Nomenclature: | 0 (DNA-Binding Proteins) RBZ1571X5H (Dasatinib) 0 (Senotherapeutics) 9IKM0I5T1E (Quercetin) 0 (Tardbp protein, mouse) |
| Entry Date(s): | Date Created: 20260918 Date Completed: 20261003 Latest Revision: 20261003 |
| Update Code: | 20261004 |
| DOI: | 10.1016/j.nbd.2026.107610 |
| PMID: | 42759848 |
| Βάση Δεδομένων: | MEDLINE |
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