UA-30 ameliorates motor deficits through RalA-mediated mitophagy in ALS mice
Bingge Zhang, Ye He, Ting Su, Xiaomei Li, Xiufen Zhang, Ruijuan Liu, Xiao Han, Ruiming Zhang, Chao Yang, Xinlei Liu, Qinghua Hou, Zaijun Zhang, Yongmei Xie, Gongping Liu, Xifei Yang
Bingge Zhang, Ye He, Ting Su, Xiaomei Li, Xiufen Zhang, Ruijuan Liu, Xiao Han, Ruiming Zhang, Chao Yang, Xinlei Liu, Qinghua Hou, Zaijun Zhang, Yongmei Xie, Gongping Liu, Xifei Yang
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Research Article Cell biology Neuroscience

UA-30 ameliorates motor deficits through RalA-mediated mitophagy in ALS mice

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, skeletal muscle atrophy, paralysis, and eventually death. Mitochondrial dysfunction plays a pivotal role in ALS pathogenesis, although the precise pathogenic mechanisms remain elusive, and effective therapeutic strategies are extremely limited. In this study, we developed a small-molecule inhibitor, UA-30, which directly targets RalA, and explored its potential for the treatment of ALS. We found that when administered via oral gavage for 6 weeks following the onset of motor deficit, UA-30 extended lifespan and improved motor function of SOD1G93A mice, a model of ALS. UA-30 ameliorated motor neuron loss, neuroinflammation, fibrosis, and mitochondrial dysfunction, as evidenced by energy recovery, decreased oxidative stress, and enhanced mitophagy. Mechanistically, UA-30 inhibited RalA activity and thereby modulated ERK/FOXO3a signaling, which inhibited FOXO3a degradation via the ubiquitin-proteasome pathway; enhanced FOXO3a stability; and upregulated the expression of mitophagy-related genes in this ALS mouse model. The beneficial effects of UA-30 in ALS were abolished by overexpression of the constitutively active form of RalA (RalAG23V) or Mdivi-1 treatment. These findings support RalA inhibition as a therapeutic strategy for enhancing mitophagy and mitigating ALS-like pathology and support UA-30 as an orally active candidate for further preclinical development.

Authors

Bingge Zhang, Ye He, Ting Su, Xiaomei Li, Xiufen Zhang, Ruijuan Liu, Xiao Han, Ruiming Zhang, Chao Yang, Xinlei Liu, Qinghua Hou, Zaijun Zhang, Yongmei Xie, Gongping Liu, Xifei Yang

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Figure 1

UA-30 treatment improved motor dysfunction and increased lifespan in male SOD1G93A mice.

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UA-30 treatment improved motor dysfunction and increased lifespan in mal...
(A) Schematic of the experimental protocol and administration schedule. (B–F) Motor performance and muscular strength assessments in male SOD1G93A mice treated with different doses of UA-30 or saline for 6 weeks. Tests performed: pole climbing (B), wire hanging (C), grip strength (D), rotarod (E), and gait (F). Representative marker paw prints in gait analysis and statistics on left/right forelimb and left/right hind limb stride length. n = 8 male mice per group. (G) Kaplan-Meier survival curves for male SOD1G93A mice treated with saline, UA-30 (100 mg/kg), or riluzole (10 mg/kg). Statistical summaries show overall lifespan for each cohort. n = 17 SOD1G93A male mice. n = 14 SOD1G93A + UA-30 male mice, n = 13 SOD1G93A + riluzole male mice. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. B–F, 1-way ANOVA followed by Tukey’s multiple-comparison test; G, log-rank (Mantel-Cox) test for survival curves and 1-way ANOVA followed by Tukey’s multiple-comparison test for overall lifespan summary.