Glycogen synthase kinase-3beta: a setpoint for dopamine dysfunction in neuroAIDS

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DESCRIPTION (provided by applicant): HIV-associated neurologic disease (HAND) remains a source of significant morbidity, and is increasing in prevalence, despite success reducing viral load in HIV-infected individuals with highly active antiretroviral therapy (HAART). While HAART can frequently delay the onset or progression of HAND, and may in part reverse the course of HAND with timely initiation, it cannot always prevent HAND, and it cannot forever halt the course of HAND as HIV-infected individuals age, thus accounting for HAND's increased prevalence. Therefore exceptional need remains for adjunctive therapies that can directly address the neurologic deficits of the increasing and aging population of HIV-infected individuals. A large body of evidence suggests HAND pathogenesis results from a toxic milieu of secretory neurotoxins secreted from HIV-1 infected, brain-resident mononuclear phagocytes and glia, which act in concert to impart a range of toxic effects neuronal function, particularly synaptic function. Neuropathologic studies demonstrating neuronal apoptosis in brain tissue of patients that had neurologic deficits indicate that the degree of frank neuronal loss does not correlate well with pre-mortem neuropsychologic deficits. Rather, alterations in dendritic architecture and synaptic structure correlate far better with these deficits, and our laboratory and others have shown that the HIV neurotoxins Tat and platelet activating factor (PAF) adversely affect synaptic function, and may even render "normal" physiologic synaptic activity harmful in their presence. From this convergent evidence, we believe HAND arises from a reversible metabolic synaptic dysfunction, and is amenable to direct therapeutic intervention. The dopamine system appears particularly vulnerable in HAND, and there is evidence that a "reversible" synaptic dysfunction applies to dopaminergic synapses as well. Supported by others' complementary findings, we present a breadth of preliminary evidence here that dopamine transporter (DAT) activity and function is disrupted by the HIV neurotoxin Tat, resulting in hyperactive DAT activity and dopamine uptake at the synapse. We hypothesize this hyperactive DAT activity is: 1. Sufficient in itself to cause HAND deficits, and 2. May ultimately result in permanent nigral or striatal neuronal loss and neurologic deficit, consequent to unsustainable metabolic demands and/or enhanced auto-oxidative dopamine toxicity pre-synaptically, or over/under-stimulation of post-synaptic striatal connections. Mechanistically, binding of alpha-synuclein to DAT has been shown to increase membrane DAT in models of Parkinson's disease (PD). Separately, we have found significant roles for glycogen kinase three-beta (GSK-3beta) in models of HAND, and others' have implicated GSK-3beta in controlling alpha-synuclein activity. No direct links have yet been established between GSK and synuclein as mediators of DAT dysfunction in HAND (or PD), despite preliminary success of GSK- blockade as a potential therapeutic approach for HAND. The studies herein propose to explore these interactions as a possible root cause of dopaminergic dysfunction in neuroAIDS. PUBLIC HEALTH RELEVANCE This project proposes to study the mechanisms by which HIV-neurotoxins in the brain alter dopaminergic synapses, particularly activity of the dopamine transporter, to impart neurologic deficits in HIV Dementia, with the goal of developing adjunctive therapeutics for this disease.