Mishandling of synaptic DA and the toxic byproducts of its metabolism in the cytosol have a long history of association with the vulnerability of these neurons (e.g., Perez and Hastings, 2004; Segura-Aguilar et al., 2014). Studies of transgenic mice deficient in α-syn, while free of overt DA neuron pathology in adulthood, exhibit changes in DA neurotransmission, with some of these becoming exaggerated in aged animals. Adult, triple knock-out mice for all synuclein family proteins exhibit elevated evoked release of DA in striatum, enhanced turnover and reduced presynaptic DA stores (Anwar et al., 2011). Study of two α-syn deficient mouse lines found evidence for increased stimulated DA overflow in striatum, higher basal extracellular DA levels, decreased expression of the dopamine transporter (DAT) and reduced DA reuptake (Chadchankar et al., 2011). Aged (24–26 months old) α-syn null mice exhibit significant reduction of striatal DA, a decrease in TH+ fibers and decreased striatal levels of TH and DAT (Al-Wandi et al., 2010). These data support the view that α-syn is a pivotal presynaptic regulator of DA neurotransmission and that disruption of this process may result in chronic accumulation of DA in the cytosol.