Locomotor activity and evoked dopamine release are reduced in mice overexpressing A30P-mutated human alpha-synuclein.
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.
Yavich
Leonid
L
Department of Pharmacology and Toxicology, University of Kuopio, FIN-70211 Kuopio, Finland. leonid.yavich@uku.fi
Oksman
Mari
M
Tanila
Heikki
H
Kerokoski
Petri
P
Hiltunen
Mikko
M
van Groen
Thomas
T
Puoliväli
Jukka
J
Männistö
Pekka T
PT
García-Horsman
Arturo
A
MacDonald
Ewen
E
Beyreuther
Konrad
K
Hartmann
Tobias
T
Jäkälä
Pekka
P
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*
D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D051844:alpha-Synuclein; D019805:alpha-Methyltyrosine; D004298:Dopamine