ArticleFrontiers in pharmacology2026
Therapeutic potential of the Nrf2 activator omaveloxolone in spinocerebellar ataxia type 3 in cellular and
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominant polyglutamine neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3). Mutant ataxin-3 accumulation, oxidative stress, mitochondrial dysfunction, and impaired protein quality control contribute to its pathogenesis; however, no disease-modifying therapy is currently available. Omaveloxolone (RTA-408), an activator of nuclear factor erythroid 2-related factor 2 (Nrf2), is approved for Friedreich's ataxia, but its therapeutic potential in SCA3 remains unclear. Methods: We evaluated the effects of RTA-408 in MJD78 cells and Drosophila SCA3 models. Cell viability, apoptosis, mutant ataxin-3 levels, Nrf2-associated antioxidant proteins, p62/autophagy-related markers, and mitochondrial phenotypes were assessed in MJD78 cells. Survival, climbing ability, and external eye degeneration were evaluated in SCA3tr-Q78 flies. Results: In MJD78 cells, 0.3 and 0.5 μM RTA-408 more consistently improved cell viability, reduced apoptosis, and decreased detectable mutant ataxin-3 accumulation than 0.1 μM RTA-408. RTA-408 increased the nuclear-to-cytoplasmic Nrf2 ratio and upregulated NQO1, HO-1, and SOD2 without significantly altering intracellular or mitochondrial reactive oxygen species levels. RTA-408 also increased p62 expression, whereas ATG7, Beclin 1, LAMP2, and the LC3-II/LC3-I ratio showed limited or nonsignificant changes, indicating p62 upregulation without definitive evidence of canonical autophagic flux activation. In addition, 0.3 μM RTA-408 partially shifted mitochondrial morphology from globe-like to elongated forms and increased mitochondrial DNA copy number. In SCA3tr-Q78 flies, RTA-408 partially improved survival, locomotor performance, eye size, and pigmentation, with more evident benefits at earlier stages. Conclusion: These findings support the protective potential of RTA-408 in SCA3-related models. Its effects were associated with activation of Nrf2-related antioxidant responses, p62 upregulation, and selected improvements in mitochondrial phenotypes. Further studies are needed to clarify the underlying mechanisms and determine the translational potential of RTA-408 for SCA3.
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