Gamma-Synuclein-Mediated Regulation of Norepinephrine Transporter

人类大脑中异常的去甲肾上腺素[NE]神经传递与情绪障碍、抑郁症、药物成瘾和神经退行性疾病有关。β-突触核蛋白[β-Syn]是突触核蛋白家族的一员，在单胺能神经元中表达，但其在脑中的功能尚不清楚。我们已经表明，β-Syn可以通过与微管[MT]细胞骨架的相互作用来调节NE转运蛋白[NET]的功能和运输。我们在这里表明，E-Syn也可以调节这些NET活动。这种由N-Syn进行的调制是NET所独有的。在抑郁症大鼠模型中，存在β-Syn的过表达，导致NET功能和运输失调，并且对诺考达唑[一种MT去稳定剂]的作用无反应，这可能是由于β-Syn/NET复合物与MT细胞骨架的紧密结合.用地昔帕明[一种NET阻断剂]长期治疗这些动物降低了β-Syn蛋白表达，同时增加了β-Syn水平，使NET受到β-Syn的适当调节，并完全恢复了诺考达唑的敏感性。在抑郁症患者的死后大脑中，我们也发现了β-Syn的过度表达，这为β-Syn在人类抑郁症的发生和维持中的作用增加了临床意义。 我们假设，β-Syn作为一个profetin，β-Syn/β-Syn表达水平的不平衡是抑郁症的发生中心。当过表达时，β-Syn覆盖β-Syn对NET的规范性调节。 因此，靶向β-Syn表达水平可能是控制人类抑郁症的关键。我们将在此详细研究地昔帕明在体外和体内模型中降低β-Syn水平的细胞和分子机制，所述模型在β-Syn存在或不存在的情况下单独表达β-Syn或同时表达β-Syn和NET.我们还将分析其他NET抗抑郁药在体外模型中降低β-Syn表达的机制。最后，我们将测量过表达β-Syn的转基因小鼠以及β-Syn敲除小鼠对NET抗抑郁药的神经化学和行为反应。通过这些研究，我们将能够评估β-Syn表达调节的机制，以及确定这种调节在抑郁症发生中的生理病理学相关性。

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.