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J Biol Chem. 2012 Jan 27;287(5):2971-83. doi: 10.1074/jbc.M111.308312. Epub 2011 Nov 29.

Hypokinesia and reduced dopamine levels in zebrafish lacking β- and γ1-synucleins.

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1
Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.

Abstract

α-Synuclein is strongly implicated in the pathogenesis of Parkinson disease. However, the normal functions of synucleins and how these relate to disease pathogenesis are uncertain. We characterized endogenous zebrafish synucleins in order to develop tractable models to elucidate the physiological roles of synucleins in neurons in vivo. Three zebrafish genes, sncb, sncg1, and sncg2 (encoding β-, γ1-, and γ2-synucleins respectively), show extensive phylogenetic conservation with respect to their human paralogues. A zebrafish α-synuclein orthologue was not found. Abundant 1.45-kb sncb and 2.7-kb sncg1 mRNAs were detected in the CNS from early development through adulthood and showed overlapping but distinct expression patterns. Both transcripts were detected in catecholaminergic neurons throughout the CNS. Zebrafish lacking β-, γ1-, or both synucleins during early development showed normal CNS and body morphology but exhibited decreased spontaneous motor activity that resolved as gene expression recovered. Zebrafish lacking both β- and γ1-synucleins were more severely hypokinetic than animals lacking one or the other synuclein and showed delayed differentiation of dopaminergic neurons and reduced dopamine levels. Phenotypic abnormalities resulting from loss of endogenous zebrafish synucleins were rescued by expression of human α-synuclein. These data demonstrate that synucleins have essential phylogenetically conserved neuronal functions that regulate dopamine homeostasis and spontaneous motor behavior. Zebrafish models will allow further elucidation of the molecular physiology and pathophysiology of synucleins in vivo.

PMID:
22128150
PMCID:
PMC3270954
DOI:
10.1074/jbc.M111.308312
[Indexed for MEDLINE]
Free PMC Article
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