Sumoylation profiles and mitochondrial dynamics in in vivo and in vitro models of Parkinson's disease.

Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss and motor and non-motor impairments. Mitochondrial dysfunction and altered post-translational modifications, including SUMOylation, have emerged as key mechanisms in PD pathogenesis. Here, we investigated global SUMOylation changes in in vivo and in vitro PD models induced by MPTP and MPP+, respectively. Intranasal MPTP administration in rats induced region- and time-dependent changes in Ubc9 and SENP3 across the olfactory bulb, prefrontal cortex, striatum, and hippocampus. In primary cortical neurons, MPP+ reduced SUMO-2/3 conjugation, Ubc9 and SENP3 levels, along with the mitochondrial fission proteins Drp1 and Mff. Notably, SENP3 showed opposite regulation in vivo and in vitro, highlighting model-specific SUMOylation responses to neurotoxic stress. These findings suggest that context-dependent alterations in SUMOylation and mitochondrial dynamics contribute to PD pathogenesis.