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Targeted Atp1a2 knockdown by antisense oligonucleotides leads to reduced SOD1 aggregation and accelerated disease progression in the SOD1*G93A mouse model of ALS
Author(s) -
Iyer Abhirami Kannan,
Schoch Kathleen M.,
Oldenborg Anna,
Chen Hao,
Smith Sarah E,
Miller Timothy M,
Karch Celeste M.,
Bonni Azad
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.058737
Subject(s) - sod1 , gene knockdown , amyotrophic lateral sclerosis , medicine , chemistry , disease , apoptosis , biochemistry
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.