Gamma-Synuclein-Mediated Regulation of Norepinephrine Transporter

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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.