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Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy
Rachael A. Powis, … , Mimoun Azzouz, Thomas H. Gillingwater
Rachael A. Powis, … , Mimoun Azzouz, Thomas H. Gillingwater
Published July 21, 2016
Citation Information: JCI Insight. 2016;1(11):e87908. https://doi.org/10.1172/jci.insight.87908.
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Research Article Neuroscience Therapeutics

Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy

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Abstract

The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA. Loss of UBA1 was a conserved response across mouse and zebrafish models of SMA as well as in patient induced pluripotent stem cell–derive motor neurons. Restoration of UBA1 was sufficient to rescue motor axon pathology and restore motor performance in SMA zebrafish. Adeno-associated virus serotype 9–UBA1 (AAV9-UBA1) gene therapy delivered systemic increases in UBA1 protein levels that were well tolerated over a prolonged period in healthy control mice. Systemic restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular and organ pathology. AAV9-UBA1 therapy was also sufficient to reverse the widespread molecular perturbations in ubiquitin homeostasis that occur during SMA. We conclude that UBA1 represents a safe and effective therapeutic target for the treatment of both neuromuscular and systemic aspects of SMA.

Authors

Rachael A. Powis, Evangelia Karyka, Penelope Boyd, Julien Côme, Ross A. Jones, Yinan Zheng, Eva Szunyogova, Ewout J.N. Groen, Gillian Hunter, Derek Thomson, Thomas M. Wishart, Catherina G. Becker, Simon H. Parson, Cécile Martinat, Mimoun Azzouz, Thomas H. Gillingwater

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Figure 1

UBA1 loss in patient-derived iPSC motor neurons and SMA zebrafish, with rescue of zebrafish motor pathology following Uba1 restoration.

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UBA1 loss in patient-derived iPSC motor neurons and SMA zebrafish, with ...
(A–C) Significant reduction of survival motor neuron (SMN) and ubiquitin-like modifier activating enzyme 1 (UBA1) protein in type I spinal muscular atrophy (SMA) patient iPSC-derived motor neurons, as quantified by Western blot (independent clones per genotype: control n = 9 and SMA n = 8; unpaired, 2-tailed Student’s t test). (D–F) Significant reduction in Smn and Uba1 protein levels in zebrafish injected with 6 ng morpholino oligonucleotide (MO) targeted against Smn compared to uninjected controls, as quantified Western blot analysis (n = 3, batches of 30 fish per lane; unpaired, 2-tailed Student’s t test). Lanes were run on the same gel but were noncontiguous. (G) Representative micrographs of spinal motor axons from uninjected control zebrafish, zebrafish injected with 4 ng Smn MO (white arrow indicates abnormal axon branching, gray arrow indicates severely truncated axons), and zebrafish injected with 4 ng Smn MO coinjected 200 ng/μl human UBA1 mRNA at 30 hours after fertilization (scale bar: 50 μm). (H–J) Significant improvement in the percentage of normal, branched, and severely truncated motor axons in zebrafish injected with 4 ng Smn MO coinjected 200 ng/μl human UBA1 mRNA (n = 20 per treatment group; 1-way ANOVA with Tukey’s post-hoc test). (K) Representative tracings of automated swim path analysis of uninjected control zebrafish, zebrafish injected with 4 ng Smn MO, and zebrafish injected with 4 ng Smn MO coinjected 200 ng/μl human UBA1 mRNA at 3 days after fertilization (scale bar: 1 cm). (L) Significant improvement in the number of quadrants entered during automated swim path analysis of zebrafish injected with 4 ng Smn MO coinjected 200 ng/μl human UBA1 mRNA (control n = 18, Smn MO n = 33, Smn MO + UBA1 n = 32; Kruskal-Wallis test with Dunn’s post-hoc test). *P ≤ 0.05, **P ≤ 0.01, ****P ≤ 0.001.

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