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In this study, we showed that perillaldehyde (PAE), a natural occurring compound, bound directly to the core protein of SGs, Ras GTPase\u2010activating protein\u2010binding 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\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    (\n                    <jats:italic>C. elegans<\/jats:italic>\n                    ) and mice, PAE administration prompted SG formation, enhanced eIF2\u03b1 phosphorylation, shielded dopaminergic neurons from toxic insults, mitigated \u03b1\u2010synuclein (\u03b1\u2010syn) aggregation, and improved PD\u2010like 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 \u03b1\u2010syn aggregation in cells and worms. Notably, the inhibition of SG assembly via\n                    <jats:italic>gtbp\u20101<\/jats:italic>\n                    and\n                    <jats:italic>tiar\u20101<\/jats:italic>\n                    RNAi effectively counteracted the beneficial effects of PAE in\n                    <jats:italic>C. elegans<\/jats:italic>\n                    . Collectively, these results imply that PAE may exert neuroprotective effects by targeting G3BP\u2010mediated SG formation, thereby safeguarding dopaminergic neurons from toxic damage.\n                  <\/jats:p>","DOI":"10.1002\/advs.202412152","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T10:31:56Z","timestamp":1739529116000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Perillaldehyde Improves Parkinson\u2010Like Deficits by Targeting G3BP Mediated Stress Granule Assembly in Preclinical Models"],"prefix":"10.1002","volume":"12","author":[{"given":"Minglv","family":"Fang","sequence":"first","affiliation":[{"name":"School of Pharmacy Shanghai University of Traditional Chinese Medicine  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Pharmacy Shanghai 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