Gamma-Synuclein-Mediated Regulation of Norepinephrine Transporter

人脑中异常的去甲肾上腺素[NE]神经传递与情绪障碍、抑郁、药物成瘾和神经退行性疾病有关。􀈖-synuclein[􀈖-Syn]是突触核蛋白家族的一员，在单胺能神经元中表达，但其在大脑中的功能尚不清楚。我们已经证明􀄮-Syn可以通过与微管细胞骨架的相互作用来调节NE转运体[NET]的功能和运输。我们在这里展示了􀈖-Syn也可以调节这些。NET活动。􀈖-Syn的这种调制是。NET独有的。在抑郁症大鼠模型中，􀈖-Syn过表达，导致NET功能和运输失调，对nocodazole[一种MT不稳定剂]的作用没有反应，可能是由于􀈖-Syn/NET复合物与MT细胞骨架紧密结合。用地西帕明[一种NET阻滞剂]对这些动物进行慢性治疗，可降低􀈖-Syn蛋白表达，同时增加􀄮-Syn水平，使NET受到􀄮-Syn的适当调节，并完全恢复诺可达唑的敏感性。在抑郁症患者死后的大脑中，我们也发现􀈖-Syn过度表达，增加了􀈖-Syn在人类抑郁症发生和维持中的作用的临床相关性。

Aberrant norepinephrine [NE] neurotransmission in the human brain is linked to mood disorders, depression, drug addiction and neurodegenerative diseases. 􀈖-synuclein [􀈖-Syn], a member of the synuclein family of proteins, is expressed in monoaminergic neurons, but its function in the brain is not known. We have shown that 􀄮-Syn can modulate the function and trafficking of the NE transporter [NET], through interactions with the microtubule [MT] cytoskeleton. We show here that 􀈖-Syn can also regulate these NET activities. Such modulation by 􀈖-Syn is unique to NET. In a rat model of depression, there is overexpression of 􀈖-Syn, causing NET function and trafficking to be dysregulated and unresponsive to the effects of nocodazole [a MT destabilizing agent], probably due to tight binding of the 􀈖-Syn/NET complex to the MT cytoskeleton. Chronic treatment of these animals with desipramine [a NET blocker] reduces 􀈖-Syn protein expression, while increasing 􀄮-Syn levels, permitting NET to be appropriately regulated by 􀄮-Syn, with full restoration of nocodazole sensitivity. In postmortem brains from patients with depression, we also show that 􀈖-Syn is overexpressed, adding clinical relevance for a role for 􀈖-Syn in the genesis and maintenance of depression in humans. We hypothesize that 􀈖-Syn acts as a prodepressant, and that imbalances in 􀈖-Syn/􀄮-Syn expression levels is central to the genesis of depression. When overexpressed, 􀈖-Syn overrides the normative regulation of NET by 􀄮-Syn. Therefore, targeting 􀈖-Syn expression levels may be key to controlling depression in humans. We will investigate here in detail the cellular and molecular mechanisms by which desipramine reduces 􀈖-Syn levels in both in vitro and in vivo models, which express either 􀈖-Syn alone or both 􀈖-Syn and NET, in the presence or absence of 􀄮-Syn. We will also analyze the mechanisms by which other NET antidepressants decrease 􀈖-Syn expression in in vitro models. Finally, we will measure neurochemical and behavioral responses to NET antidepressants in 􀄮-Syn overexpressing transgenic mice, as well as in 􀄮-Syn knock-out mice. From these studies we will be able to assess the mechanisms by which 􀈖-Syn expression is regulated as well as ascertain the physiopathological relevance of such regulation in the genesis of depression.