Autor: |
Iyer, Abhirami K., Schoch, Kathleen M., Verbeck, Anthony, Galasso, Grant, Chen, Hao, Smith, Sarah, Oldenborg, Anna, Miller, Timothy M., Karch, Celeste M., Bonni, Azad |
Předmět: |
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Zdroj: |
PLoS ONE; 11/28/2023, Vol. 18 Issue 11, p1-27, 27p |
Abstrakt: |
Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases. [ABSTRACT FROM AUTHOR] |
Databáze: |
Complementary Index |
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