title: Locomotor activity and evoked dopamine release are reduced in mice overexpressing A30P-mutated human alpha-synuclein.
abstract: We have generated a transgenic mouse line overexpressing mutated human A30P alpha-synuclein under the control of the prion-related protein promoter. Immunohistology revealed mutated human A30P alpha-synuclein protein in numerous brain areas, but no gross morphological changes, Lewy bodies, or loss of dopaminergic cell bodies. The transgenic mice displayed decreased locomotion, impaired motor coordination, and balance. In vivo voltammetry showed that A30P mice responded to longer stimulation of the ascending dopaminergic pathways with less dopamine release in striatum and had a slower rate of dopamine decline after repeated stimulations or after alpha-methyl-p-tyrosine-HCl treatment. However, dopamine re-uptake or transporter levels were similar in transgenic and control mice. Our data provide evidence that overexpression of mutated human A30P alpha-synuclein in mice leads to a reduced size of the dopamine storage pool. This is in agreement with the previously postulated involvement of alpha-synuclein in the turnover of transmitter vesicles and may explain the observed motor deficits in A30P mice.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kuopio, FIN-70211 Kuopio, Finland. leonid.yavich@uku.fi
authors.forename: Leonid
authors.initials: L
authors.lastname: Yavich
authors.forename: Mari
authors.initials: M
authors.lastname: Oksman
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Petri
authors.initials: P
authors.lastname: Kerokoski
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
authors.forename: Thomas
authors.initials: T
authors.lastname: van Groen
authors.forename: Jukka
authors.initials: J
authors.lastname: Puoliväli
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Männistö
authors.forename: Arturo
authors.initials: A
authors.lastname: García-Horsman
authors.forename: Ewen
authors.initials: E
authors.lastname: MacDonald
authors.forename: Konrad
authors.initials: K
authors.lastname: Beyreuther
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
authors.forename: Pekka
authors.initials: P
authors.lastname: Jäkälä
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D013378:Substantia Nigra / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D019805:alpha-Methyltyrosine / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D051844:alpha-Synuclein; D019805:alpha-Methyltyrosine; D004298:Dopamine