Perillaldehyde Improves Parkinson‐Like Deficits by Targeting G3BP Mediated Stress Granule Assembly in Preclinical Models

Stress granules (SGs) fulfill a pivotal role in host defense mechanisms, by sequestering both mRNA and protein via the process of liquid-liquid phase separation (LLPS). In this study, we showed that perillaldehyde (PAE), a natural occurring compound, bound directly to the core protein of SGs, Ras GTPase-activating protein-binding protein 1/2 (G3BP1/2), thereby inducing the assembly of SGs through the LLPS of G3BP/RNA complexes in vitro. Moreover, in Parkinson's disease (PD) models using Caenorhabditis elegans (C. elegans) and mice, PAE administration prompted SG formation, enhanced eIF2α phosphorylation, shielded dopaminergic neurons from toxic insults, mitigated α-synuclein (α-syn) aggregation, and improved PD-like motor disorders. In addition, these findings revealed that the interaction between G3BP1 and histone deacetylase 6 (HDAC6) inhibited the functions of cytoplasmic HDAC6 and reduced α-syn aggregation in cells and worms. Notably, the inhibition of SG assembly via gtbp-1 and tiar-1 RNAi effectively counteracted the beneficial effects of PAE in C. elegans. Collectively, these results imply that PAE may exert neuroprotective effects by targeting G3BP-mediated SG formation, thereby safeguarding dopaminergic neurons from toxic damage.