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SUMMARY:Pre-degenerative deficits in dopamine transmission in an alpha-syn
 uclein mouse model of Parkinson’s disease: the role of lipids and the do
 pamine transporter - Sarah Threlfell\, Senior Research Fellow\, Dept. Phys
 iology\, Anatomy and Genetics\, University of Oxford\, Oxford Parkinson’
 s Disease Centre
DTSTART:20170927T113000Z
DTEND:20170927T123000Z
UID:TALK83821@talks.cam.ac.uk
CONTACT:Patrick Flagmeier
DESCRIPTION:Motor symptoms in Parkinson’s disease (PD) arise following t
 he degeneration of dopamine (DA) neurons in the substantia nigra pars comp
 acta (SNc). These nigrostriatal neurons have huge axonal arbors projecting
  to dorsal striatum where DA is released and exerts its effect upon striat
 al projection neurons to regulate motor output. \nIn a mouse model of earl
 y Parkinson’s disease where human α-synuclein is overexpressed (SNCA-OV
 X) we see an age-dependent loss of DA neurons and emergence of motor dysfu
 nction alongside changes in DA neuron firing properties. Interestingly\, p
 rior to neurodegeneration or behavioural changes one of the earliest chang
 es 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 st
 riatum\, a region predominantly innervated by more PD-vulnerable SNc DA ne
 urons\, and less pronounced in ventral striatal regions. These data sugges
 t that early changes in DA synapse function which predate neurodegeneratio
 n may contribute to the subsequent demise of these neurons. \nDeficits in 
 DA release are present throughout the SNCA-OVX lifespan (3-22 months). Def
 icits in evoked extracellular DA ([DA]o) are not attributable to any defic
 iency in DA content or any detectable increase in rate of DA uptake under 
 control conditions. However\, inhibitors of DA uptake\, cocaine and GBR 12
 935\, increase [DA]o to a greater extent in dorsal striatum of SNCA-OVX mi
 ce than Snca (-/-) controls. Furthermore\, DAT inhibitors eliminate defici
 ts 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 e
 nhanced roles for serotonin or norepinephrine transporters. However\, func
 tional 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 di
 srupting synuclein:lipid interactions might provide a useful future neurop
 rotective strategy.\n
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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