Deep brain stimulation (DBS) of the subthalamic nucleus (STN) modulates dysfunctional neuronal activity in central motor networks. However, it is uncertain whether chronic DBS has a disease-modifying effect on the progressive course of Parkinson’s disease (PD). Here, we will first characterize the “natural” disease course in a viral vector-driven, A53T mutant, α-synuclein-overexpression PD rat model by longitudinal assessment of clinical symptoms and disease biomarkers, and later intervene with either DBS or pharmacotherapy at different disease stages. We want to provide preclinical evidence for disease modification, identify the underlying mechanisms, and provide a rationale for a future clinical neuroprotection trial in patients.