Abstract
Synaptic re-uptake of dopamine is dependent on the dopamine transporter (DAT), which is regulated by its distribution 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 not known. Here we use SH-SY5Y cells as a model of DAT trafficking to demonstrate that all three synucleins negatively regulate cell surface distribution of DAT. Under these conditions the synucleins limit export of DAT from the endoplasmic reticulum (ER) by impairment of the ER-Golgi transition, leading to accumulation of DAT in this compartment. This mechanism for regulating DAT export indirectly through effects on ER and Golgi function represents a previously unappreciated role for the extended synuclein family that is likely applicable to trafficking of the many proteins that rely on the secretory pathway.
Highlights
The synuclein (Syn) family of proteins includes three paralogous isoforms alpha (a-Syn), beta (b-Syn), and gamma (c-Syn) and represents a unique class of abundant brain proteins. a-Syn is closely associated with the neurodegenerative pathology of Parkinson’s disease (PD), and is linked to both autosomal dominant [1,2,3,4] and idiopathic [5] forms of the disease
We demonstrate for the first time that both b-Syn and c-Syn can modulate dopamine transporter (DAT) trafficking in a manner that is subtly different from a-Syn
These prior findings raise the possibility that a compensatory response occurs in these animals, potentially due to redundancy between the Syn proteins. [3H]-DA uptake by DAT is dependent on localization of the transporter to the plasma membrane and is reduced by a-Syn trafficking of DAT away from the cell surface and into the cytoplasm [28,29,46,47,48]
Summary
The synuclein (Syn) family of proteins includes three paralogous isoforms alpha (a-Syn), beta (b-Syn), and gamma (c-Syn) and represents a unique class of abundant brain proteins. a-Syn is closely associated with the neurodegenerative pathology of Parkinson’s disease (PD), and is linked to both autosomal dominant [1,2,3,4] and idiopathic [5] forms of the disease. The Syn proteins have been defined as modulators of synaptic function, with many proposed mechanisms of action, including chaperoning of membrane fusion complexes and maintenance of the synaptic integrity that is essential for neurotransmission [11,12]. We have shown that an important function of the Syns is the regulation of the synaptic content of neurotransmitters through modulation of monoamine transporter (MAT) re-uptake activity, trafficking, and plasma membrane distribution [21]. As MAT are the sole determinants of neurotransmitter re-uptake, the modulation of the transporters of dopamine (DAT), norepinephrine (NET), and serotonin (SERT) by the Syn is an important neuroregulatory function that has implications for PD as well as neuropsychiatric disorders, including depression, anxiety, sleep and attention deficit disorders, and drug addiction
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