Targeting senescence in Amyotrophic Lateral Sclerosis- senolytic treatment improves neuromuscular function and preserves cortical excitability in a TDP-43Q331K mouse model

Authors
Jose A Viteri, Nathan R Kerr, Charles D Brennan, Grace R Kick, Meifang Wang, Arsh Ketabforoush, Harper K Snyder, Peter J Moore, Fereshteh B Darvishi, Anna Roshani Dashtmian, Sindhuja N Ayyagari, Kelly Rich, Yi Zhu, W David Arnold


Lab

Journal
Research Square

Abstract
(A) Cortical senescencemarkers (P21, BCL1, IL-lβ, BCL-w, BCL2, P53,andBcl-xL) were quantified using digital PCR and normalized toGAPDH. TDP-43-vehicle mice exhibited elevated levels ofP21, BCL2, P53,andIL1βcompared to controls. Treatment with senolytics significantly reduced P21,BCL2,andP53levels compared to TDP-43-vehicle mice normalizing these markers to control levels, whileIL-lβremained elevated.BCL1was elevated in TDP-43-senolytic mice compared to controls but showed no significant difference from TDP-43-vehicle mice. Cortical TDP-43 expression, assessed via human TDP-43(h-TARDBP)transcript levels, was significantly elevated in TDP-43-vehicle and TDP-43-senolytic mice compared to controls, with TDP-43-senolytic mice showing further increases. (B) Axonal damage, represented by serum neurofilament light (NfL) levels, was significantly elevated in TDP-43-vehicle mice compared to controls at the mid-time point and at the final time point. Senolytic treatment significantly reduced NfL levels at the final time point compared to TDP-43-vehicle mice, though levels remained higher than controls. (C-D) P21 (red), a marker of cell-cycle arrest, is significantly increased in TDP-43-vehicle mice compared to controls. Senolytic treatment significantly reduces P21 expression, and normalizes levels compared to controls. BCL2 (green), an anti-apoptotic protein associated with senescence, is significantly increased in TDP-43-vehicle mice compared to controls. Senolytic treatment significantly reduces BCL2 expression, and normalizes levels compared to controls. P53 (cyan), a tumor suppressor and regulator of cellular senescence, is significantly elevated in TDP-43-vehicle mice compared to controls. Senolytic treatment significantly reduces P53 expression, but levels remain elevated compared to controls. Representative images (bottom) show P21, BCL2, and P53 staining in layer V.

Keywords/Topics
ALS; aging; senescence; senolytics; motor cortex; neuromuscular

BIOSEB Instruments Used:
Grip strength test (BIO-GS4),Rotarod for rats and mice (BX-ROD)

Source :

https://pmc.ncbi.nlm.nih.gov/articles/PMC11975006/

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