Modulation of dopamine transporter trafficking by the synuclein family of proteins
Oaks, Adam W.
Dopamine signaling is controlled in part by pre-synaptic re-uptake of dopamine through the dopamine transporter (DAT), and is therefore regulated by the distribution of DAT to the cell surface. DAT trafficking is modulated by the Parkinson's disease-linked protein alpha-synuclein, but the contribution of synuclein family members beta-synuclein and gamma-synuclein to DAT trafficking is unknown. Here, both animal and cellular models of DAT trafficking have been used to examine the role of the synucleins in modulation of DAT.Over-expression of A53T mutant human alpha-synuclein is among the most successful transgenic models of Parkinson's disease, producing accumulation of A53T alpha-synuclein that causes adult mice to develop severe motor impairment resulting in early death at 8-12 months of age. Altered motor activity and anxiety-like behaviors have also been reported in pre-symptomatic animals. An analysis over the adult life-span of motor activity, anxiety-like, and depressive-like behaviors identified perturbations both before and after the onset of disease. While membrane distribution of DAT was elevated in young A53T mice, DAT function was normalized with aging, and was associated with accumulation of the synuclein proteins, activation of Tau kinases, and hyperphosphorylation of Tau. Substantia nigra pars compacta neuron counts were reduced in aged A53T mice, yet striatal medium spiny neuron dendritic spine density was maintained, suggesting that compensatory modulation of DAT by beta-synuclein and gamma-synuclein helped to preserve striatal function.To explore the mechanisms enabling synuclein modulation of DAT, the effect of each synuclein on DAT distribution was examined in SH-SY5Y human neuroblastoma cells. These studies showed that all three synucleins negatively regulated cell surface distribution of DAT and limited export of DAT from the endoplasmic reticulum (ER). These effects were associated with impairment of the ER-Golgi transition and entry of the synucleins into the ER lumen. It was shown that the synucleins bound to and altered the activity of ER resident heat shock chaperone Grp78 (78 kDa glucose-regulated protein), a critical regulator of ER function. This suggests a mechanism for regulation of export of DAT and similar cargoes by the extended synuclein family through multiple parallel impacts on cellular trafficking and the secretory pathway.
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