Fig. 1

A working model that illustrates the functional role of post translationally modified α-synuclein in normal physiology. a N-terminal acetylation of α-syn facilitates dynamin-mediated endocytosis of TfR and internalisation of iron (1). An appropriate intracellular iron level is tightly controlled to maintain neuronal function including DA production by the iron-dependent enzyme TH (2). DA is incorporated into synaptic storage vesicles through α-syn binding to VMAT2 (3). Upon stimuli, VAMP2 then binds to the t-SNARE protein to allow fusion with the synaptic membrane and release of DA into the cleft (4). Recycling of DA back into the pre-synaptic neuron through the DAT receptors also requires binding to α-syn on the membrane and subsequent reinternalisation into synaptic vesicles through the α-syn/VMAT2 complex (5). b When iron or DA transport is required to be reduced in physiological conditions, α-syn is phosphorylated or oxidised (not shown) to decrease lipid affinity. A lack of membrane bound α-syn reduces neuronal iron import through TfR endocytosis (1), production of DA by TH(2), DA incorporation into synaptic vesicles (3), reduced DA release into the synaptic cleft (4) and/or DA recycling within the presynaptic neuron (5)