ABSTRACT: The most common gene mutated in Parkinson’s disease (PD) occurs in a gene called leucine-rich repeat kinase 2 (LRRK2). The research work in Dr. Zhang’s laboratory has focused on understanding how dopamine (DA) neurons in the substantia nigra pars compacta (SNc) are uniquely sensitive to degeneration in LRRK2-mediated PD using genetic mouse models. Using cutting-edge electrophysiology and 2PLSM (Two-Photon Laser Scanning Microscope) imaging, we have found an age-dependent progressive loss of synaptic and mitochondrial functions in SNc dopaminergic neurons in the human-R1441G mouse model, which might lead to the motor deficits and neurite degeneration. Her lab has elucidated two important findings: 1) the R1441G mutation leads to presynaptic dysfunctions in DA terminals due to aberrant synaptic vesicle replenishment, which can be partially rescued by vesicular monoamine transporter 2 (VMAT2); and 2) oxidative stress in the SNc DA neurons and its projections in the dorsal striatum are specifically elevated with aging by the R1441G mutation as a result of elevated intracellular calcium levels and reduced functions of the mitochondrial uncoupling proteins.