University of Cambridge > > Biophysical Seminars > Pre-degenerative deficits in dopamine transmission in an alpha-synuclein mouse model of Parkinson’s disease: the role of lipids and the dopamine transporter

Pre-degenerative deficits in dopamine transmission in an alpha-synuclein mouse model of Parkinson’s disease: the role of lipids and the dopamine transporter

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Motor symptoms in Parkinson’s disease (PD) arise following the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). These nigrostriatal neurons have huge axonal arbors projecting to dorsal striatum where DA is released and exerts its effect upon striatal projection neurons to regulate motor output. In a mouse model of early Parkinson’s disease where human α-synuclein is overexpressed (SNCA-OVX) we see an age-dependent loss of DA neurons and emergence of motor dysfunction alongside changes in DA neuron firing properties. Interestingly, prior to neurodegeneration or behavioural changes one of the earliest changes in the DA system identified from young adulthood in SNCA OVX mice is a 30% deficit in DA transmission compared to Snca(/-) littermate controls. Moreover, this deficit is region-specific: being most marked in dorsal striatum, a region predominantly innervated by more PD-vulnerable SNc DA neurons, and less pronounced in ventral striatal regions. These data suggest that early changes in DA synapse function which predate neurodegeneration may contribute to the subsequent demise of these neurons. Deficits in DA release are present throughout the SNCA OVX lifespan (3-22 months). Deficits in evoked extracellular DA ([DA]o) are not attributable to any deficiency in DA content or any detectable increase in rate of DA uptake under control conditions. However, inhibitors of DA uptake, cocaine and GBR 12935 , increase [DA]o to a greater extent in dorsal striatum of SNCA -OVX mice than Snca (/) controls. Furthermore, DAT inhibitors eliminate deficits in DA release in dorsal striatum between SNCA -OVX and Snca (/-) mice. This was not due to changes in total DA transporter (DAT) levels, or to enhanced roles for serotonin or norepinephrine transporters. However, functional DAT in SNCA -OVX is elevated as revealed via immunofluorescence and radioligand binding studies. Preliminary data suggests that altered lipid availability in SNCA -OVX striatum might underlie the increased functional DAT in more vulnerable dorsal striatum DA axons in this PD model, thus disrupting synuclein:lipid interactions might provide a useful future neuroprotective strategy.

This talk is part of the Biophysical Seminars series.

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