Altered dopamine (DA) transporter (DAT) activity is implicated in Parkinson disease. Missense DAT mutations are directly associated with adult early-onset Parkinsonism and progressive dopaminergic neurodegeneration. Increased ?-synuclein, a protein partner of DAT, is also implicated in Parkinson disease and other neurodegenerative diseases. Over 80% of patients with longstanding Parkinson disease will develop dementia.Multiplication of ?-synuclein gene in human is involved in the development of PD and/or dementia with Lewy bodies. The long-term goal of this study is to determine how DAT dysfunction following ?-synuclein overexpression disrupts neuronal and network function, prior to cell loss. Our primary objective is to determine the underlying mechanism/s of the progression of pathology and identification of therapeutic targets. Determining the etiology of DA signaling dysfunction in Parkinson disease and other neurological disorders have been challenging as DAT regulates the spatiotemporal characteristics of DA transmission by regulating: 1) uptake of released DA, 2) spontaneous firing activity of DA neurons and 3) non-vesicular DA release (efflux). Therefore, it is critical to first dissect the pathological regulations of these functions at a single neuron, then determine the interrelated functional changes in the diseased state. Our preliminary and published data suggest there is a bidirectional interaction between DAT and ?-synuclein, where the mere existence of DAT at the neuronal membrane recruits ?-synuclein to the membrane. We found membrane recruited ?-synuclein directly interacts with DAT, alters the ionic coupling of DAT by increasing an inward depolarizing Na+ current, inhibits the DAT mediated DA uptake, increases the magnitude and duration of Ca2+ spikes in DA neurons and causes a 7-fold increase in DA efflux resulting in diminished DA recycling. These effectively challenge the regulation of synaptic DA levels in the short-term and neuronal integrity in the long-term. Our pilot data suggest this problem quickly scales up to the level of cellular activity and network function. Collectively, these data support the overarching hypothesis that increased ?-synuclein in DA neurons increases firing activity of DA neurons and DA efflux via a DAT and Ca2+-dependent mechanism leading to disruption of DA transmission and neuronal communication. To address this hypothesis, we will use molecular, pharmacological and electrophysiological approaches with particular emphasis on neurochemical and molecular mechanisms of dopamine neurotransmission.
Dopamine neurotransmission is implicated in neurological and neuropsychiatric disorders. Altered dopamine transporter activity is implicated in Parkinson disease (PD). Over 80% of patients with longstanding PD will develop dementia. Multiplication of ? synuclein gene in human is involved in the development of PD and/or dementia with Lewy bodies. ?-synuclein is associated with other neurodegenerative diseases such as PD-related pathogenic mutations in Leucine-rich repeat kinase-2. The long-term goal of this study is to determine how dopamine transporter dysfunction following ?- synuclein overexpression disrupts neuronal and network function, prior to cell loss. We will use molecular and pharmacological approaches with particular emphasis on neurochemical and molecular mechanisms of dopamine neurotransmission and signaling molecules.
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