Dopamine metabolism and selective loss of SNpc DA neurons. Cartoon proposes the accumulation of cytosolic DOPAL triggers the degeneration of SNpc DA neurons in PD. Tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) mediate the synthesis of dopamine from tyrosine (Tyr) in the cytosol. Cytosolic dopamine is then immediately sequestered into the synaptic vesicles (SVs) by dopamine transporter VMAT2 for release. DAT mediates the reuptake of dopamine from extracellular space into the DA terminals. Leakage of dopamine from SVs also contributes to the cytosolic dopamine levels. MAO and ALDH1A1 are main enzymes for the degradation of cytosolic dopamine in DA neurons. A lack of ALDH1A1 may lead to a cytotoxic build-up of DOPAL which triggers the reactive oxygen species (ROS) production, protein adducts and α-synuclein aggregation, and eventually leads to cell death.