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Targeted ASO-mediated Atp1a2 knockdown in astrocytes reduces SOD1 aggregation and accelerates disease onset in mutant SOD1 mice.
- Source :
- PLoS ONE; 11/28/2023, Vol. 18 Issue 11, p1-27, 27p
- Publication Year :
- 2023
-
Abstract
- Astrocyte-specific ion pump α2-Na<superscript>+</superscript>/K<superscript>+</superscript>-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<superscript>+</superscript>/K<superscript>+</superscript>-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<superscript>+</superscript>/K<superscript>+</superscript>-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 18
- Issue :
- 11
- Database :
- Complementary Index
- Journal :
- PLoS ONE
- Publication Type :
- Academic Journal
- Accession number :
- 173894796
- Full Text :
- https://doi.org/10.1371/journal.pone.0294731