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Background <p>Spinocerebellar ataxia type 3 (SCA3/Machado-Joseph disease), an incurable autosomal dominant neurodegenerative disorder, is caused by cytotoxic aggregation of polyglutamine-expanded ataxin-3 protein. Novel therapeutic strategies targeting its pathogenesis are urgently needed.</p> Purpose <p>Given gastrodin’s established antioxidative and neuroprotective properties, this study investigated its therapeutic potential against SCA3 pathogenesis.</p> Methods <p>Three distinct cell models including parental HEK293T, ataxin-3-15Q (physiologic), and ataxin-3-77Q (pathogenic) were employed to assess gastrodin cytotoxicity, quantify insoluble aggregate formation and measure soluble ataxin-3 levels. Mechanistic studies included antioxidant capacity assays, human phosphokinase array profiling (37 kinases) and western blot validation of MAPK pathway components.</p> Results <p>Gastrodin treatment showed no cytotoxicity, significantly suppressed ataxin-3-77Q aggregate accumulation (<i>p</i> &lt; 0.01), increased soluble ataxin-3 levels, enhanced cellular antioxidant capacity and selectively downregulated ERK1/2 and p38 proteins in MAPK pathways.</p> Conclusion <p>We provide first evidence that gastrodin mitigates polyQ-mediated proteotoxicity by reducing ataxin-3 aggregation through suppression of the ERK1/2-p38 signaling axis in cellular models, revealing a novel mechanistic basis for SCA3 therapeutic development.</p>

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Gastrodin inhibits the formation of ataxin-3 aggregates by regulating the level of ERK1/2/P38 proteins

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月19日

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  • Zijian Wang,
  • Xunhao Xiao,
  • Min Wang,
  • Ruitong Cheng,
  • Chan Wang,
  • Yingxun Liu,
  • Fengqin He,
  • Xiaodong Xie

摘要

Background

Spinocerebellar ataxia type 3 (SCA3/Machado-Joseph disease), an incurable autosomal dominant neurodegenerative disorder, is caused by cytotoxic aggregation of polyglutamine-expanded ataxin-3 protein. Novel therapeutic strategies targeting its pathogenesis are urgently needed.

Purpose

Given gastrodin’s established antioxidative and neuroprotective properties, this study investigated its therapeutic potential against SCA3 pathogenesis.

Methods

Three distinct cell models including parental HEK293T, ataxin-3-15Q (physiologic), and ataxin-3-77Q (pathogenic) were employed to assess gastrodin cytotoxicity, quantify insoluble aggregate formation and measure soluble ataxin-3 levels. Mechanistic studies included antioxidant capacity assays, human phosphokinase array profiling (37 kinases) and western blot validation of MAPK pathway components.

Results

Gastrodin treatment showed no cytotoxicity, significantly suppressed ataxin-3-77Q aggregate accumulation (p < 0.01), increased soluble ataxin-3 levels, enhanced cellular antioxidant capacity and selectively downregulated ERK1/2 and p38 proteins in MAPK pathways.

Conclusion

We provide first evidence that gastrodin mitigates polyQ-mediated proteotoxicity by reducing ataxin-3 aggregation through suppression of the ERK1/2-p38 signaling axis in cellular models, revealing a novel mechanistic basis for SCA3 therapeutic development.