A Plant Model of -Synucleinopathy: Expression of -Synuclein A53T Variant in Hairy Root Cultures Leads to Proteostatic Stress and Dysregulation of Iron Metabolism.

Synucleinopathies, typified by Parkinson's disease (PD), entail the accumulation of -synuclein (Syn) aggregates in nerve cells. Various Syn mutants, including the Syn A53T variant linked to early-onset PD, increase the propensity for Syn aggregate formation. In addition to disrupting protein homeostasis and inducing proteostatic stress, the aggregation of Syn in PD is associated with an imbalance in iron metabolism, which increases the generation of reactive oxygen species and causes oxidative stress. This study explored the impact of Syn A53T expression in transgenic hairy roots of four medicinal plants (, , , and ). In all tested plants, Syn A53T expression triggered proteotoxic stress and perturbed iron homeostasis, mirroring the molecular profile observed in human and animal nerve cells. In addition to the common eukaryotic defense mechanisms against proteostatic and oxidative stresses, a plant stress response generally includes the biosynthesis of a diverse set of protective secondary metabolites. Therefore, the hairy root cultures expressing Syn A53T offer a platform for identifying secondary metabolites that can ameliorate the effects of Syn, thereby aiding in the development of possible PD treatments and/or treatments of synucleinopathies.