Targeted Atp1a2 knockdown by antisense oligonucleotides leads to reduced SOD1 aggregation and accelerated disease progression in the SOD1*G93A mouse model of ALS. (31st December 2021)

• Record Type: Journal Article
• Authors: Iyer, Abhirami Kannan; Schoch, Kathleen M.; Oldenborg, Anna; Chen, Hao; Smith, Sarah E; Miller, Timothy M; Karch, Celeste M.; Bonni, Azad
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 9
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-31
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.058737
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease affecting the cortex, brainstem and spinal cord. In familial and sporadic ALS, the levels of a complex of α2‐Na + /K + ‐ATPase (encoded by the Atp1a2 gene) and α‐adducin are increased in the spinal cord. In the SOD1*G93A mouse model of ALS, upregulation of this complex is specifically observed in astrocytes and Atp1a2 +/‐ SOD1*G93A mice show increased mobility and lifespan than Atp1a2 +/+ littermate controls. Further, RNAi‐mediated knockdown of Atp1a2 in SOD1*G93A primary mouse astrocytes prevents cell death and dendrite degeneration in co‐cultured motor neurons. These findings suggest that Atp1a2 might represent a therapeutic target in ALS. Antisense oligonucleotides (ASOs) have emerged as a safe and effective method to modify gene expression in animal models and in the clinic. Method: Here we characterize the suitability of Atp1a2 knockdown using ASOs as a means to attenuate astrocyte‐mediated neurotoxicity in SOD1*G93A mice. Two lead ASOs targeting the 3'‐UTR of Atp1a2 and reducing Atp1a2 expression by 50‐70% were identified. These two ASOs were then tested in vivo to determine their impact on disease progression and survival in SOD1*G93A mice. Result: Atp1a2 ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo . However, Atp1a2 ASO‐treated mice exhibited significantly earlier disease onset and shorter lifespan than animals receiving control ASOs. Conclusion: Together, these results demonstrate a decoupling of SOD1 aggregation and disease course, thereby, suggesting that reducing Atp1a2 expression in adulthood may not have the same beneficial effects of gene knockout at birth in SOD1*G93A mice. Additional studies are required to understand the divergence of these effects and the efficacy of Atp1a2 as a therapeutic target in ALS.