ENOrphanet Journal of Rare Diseases | Gastrodin, a compound derived from Anemarrhena asphodeloides, inhibits ataxin-3 protein aggregation by modulating the ERK1/2/p38 signaling pathway
Date: February 22, 2026
Classification: Frontiers
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This study is the first to reveal that gastrodin reduces abnormal aggregation of mutant ataxin-3 protein by inhibiting the ERK1/2-p38 signaling axis in an SCA3 cellular model, significantly enhancing soluble protein levels and cellular antioxidant capacity, demonstrating clear neuroprotective effects.
Literature Overview
The article titled 'Gastrodin, a compound derived from Anemarrhena asphodeloides, inhibits ataxin-3 protein aggregation by modulating the ERK1/2/p38 signaling pathway', published in the journal Orphanet Journal of Rare Diseases, reviews and summarizes the therapeutic potential of gastrodin in a cellular model of spinocerebellar ataxia type 3 (SCA3). The study finds that gastrodin significantly suppresses abnormal aggregation of polyQ-expanded ataxin-3 protein, increases its solubility, and exhibits no cytotoxicity. Mechanistically, this effect depends on the downregulation of total ERK1/2 and p38 protein expression, revealing a critical role of the MAPK signaling pathway in SCA3 protein toxicity. This work provides new evidence for developing SCA3 therapeutic strategies targeting the MAPK pathway.Background Knowledge
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common autosomal dominant hereditary ataxia, caused by CAG repeat expansion in the ATXN3 gene leading to a polyglutamine (polyQ) expansion mutation in the ataxin-3 protein. The mutant protein misfolds and forms insoluble aggregates, triggering neuronal dysfunction and death. Currently, there are no disease-modifying therapies. Protein toxicity and oxidative stress are central mechanisms in SCA3 pathogenesis, which reinforce each other in a vicious cycle. Previous studies have attempted to clear aggregates by enhancing autophagy or proteasome activity, or to reduce oxidative damage using antioxidants, but these approaches are limited by blood-brain barrier penetration and safety concerns. Gastrodin is the main active component of the traditional Chinese herb Gastrodia elata, known for its antioxidant, anti-inflammatory, and neuroprotective properties. It has shown potential in inhibiting protein aggregation in models of Alzheimer’s and Parkinson’s diseases, but its role in polyQ diseases has not been previously explored. This study fills that gap by systematically evaluating the efficacy and mechanism of gastrodin in an SCA3 cellular model, offering a new perspective for drug repositioning in rare neurodegenerative diseases.
Methods and Experiments
The study used HEK293T cells to construct three models: empty vector control, physiological-length ataxin-3-15Q, and pathogenic ataxin-3-77Q. Cytotoxicity of gastrodin (5–100 µM) was assessed using CCK-8 and MTT assays. Filter trap and subcellular fractionation assays were used to detect changes in insoluble ataxin-3 aggregates. Soluble ataxin-3 protein levels were analyzed by Western blot. Cellular antioxidant activity was evaluated using a total antioxidant capacity assay kit. A human phospho-kinase array (37 kinases) was used to screen for signaling pathway changes, and Western blotting validated protein expression of key MAPK pathway molecules (ERK1/2, p38, AKT, p65). Finally, an ERK inhibitor (Temuterikib) and an AKT inhibitor (MK-2206) were used to verify the signaling dependence of gastrodin’s effects.Key Findings and Insights
Research Significance and Outlook
This study is the first to confirm that gastrodin can alleviate SCA3-related protein toxicity by inhibiting the ERK1/2-p38 signaling axis, proposing a novel drug mechanism—reducing total kinase protein levels rather than merely inhibiting phosphorylation. This offers a new perspective for targeting the MAPK pathway in polyQ diseases. Gastrodin has good blood-brain barrier permeability and a well-established clinical safety profile, supporting its further development as a candidate drug for SCA3.
However, the study was validated only in HEK293T cell models, lacking functional confirmation in patient-derived neurons or SCA3 animal models. Future research should explore the precise mechanism by which gastrodin downregulates ERK/p38, such as whether it promotes protein degradation or suppresses transcription. Additionally, how polyQ expansion interferes with p65 activation and gastrodin’s anti-inflammatory effects requires further investigation. The synergistic effects of combining ERK/p38 inhibitors with gastrodin warrant systematic evaluation to optimize therapeutic strategies.
Conclusion
This study systematically reveals the neuroprotective effects and molecular mechanisms of the natural compound gastrodin in an SCA3 cellular model. Gastrodin safely reduces abnormal aggregation of pathogenic ataxin-3 protein and increases its solubility. This effect does not rely on traditional antioxidant pathways but is achieved by specifically downregulating total ERK1/2 and p38 protein expression. Functional validation experiments show that the integrity of the ERK signaling pathway is crucial for gastrodin’s anti-aggregation effect. This finding not only broadens understanding of the role of the MAPK pathway in SCA3 pathogenesis but also provides a high-quality candidate molecule for drug repositioning. Given that gastrodin already has favorable pharmacokinetic and safety data, its translational potential in rare neurodegenerative diseases warrants further exploration. Future studies should focus on validating its efficacy in models closer to human pathology and elucidating the precise mechanisms by which it regulates kinase expression, laying the foundation for developing disease-modifying therapies.
