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

## TL;DR

Gastrodin reduces harmful protein clumps in a neurodegenerative disease by targeting specific signaling proteins.

## Contribution

This study is the first to show that gastrodin reduces ataxin-3 aggregation in SCA3 by suppressing the ERK1/2-p38 pathway.

## Key findings

- Gastrodin significantly reduced ataxin-3-77Q aggregate accumulation without cytotoxicity.
- Gastrodin increased soluble ataxin-3 levels and enhanced cellular antioxidant capacity.
- Gastrodin selectively downregulated ERK1/2 and p38 proteins in the MAPK pathway.

## Abstract

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.

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

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13023-025-04089-1.

Gastrodin’s safety profile was demonstrated in SCA3 cellular models at concentrations up to 100 µM without causing cytotoxicity.

Gastrodin significantly reduced the formation of polyQ-expanded ataxin-3 aggregates.

There was a dose-dependent increase in soluble ataxin-3 levels by gastrodin.

Gastrodin was found to attenuate SCA3 proteotoxicity in cellular models by simultaneously decreasing the total protein levels of ERK1/2 and p38.

The online version contains supplementary material available at 10.1186/s13023-025-04089-1.