ZFIN ID: ZDB-PUB-111201-3
Hypokinesia and reduced dopamine levels in zebrafish lacking beta- and gamma1-synucleins
Milanese, C., Sager, J.J., Bai, Q., Farrell, T.C., Cannon, J.R., Greenamyre, J.T., and Burton, E.A.
Date: 2012
Source: The Journal of biological chemistry   287(5): 2971-2983 (Journal)
Registered Authors: Burton, Edward A.
Keywords: animal models, dopamine, molecular biology, Parkinson's disease, synuclein, zebrafish
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Differentiation/physiology
  • Dopamine/genetics
  • Dopamine/metabolism*
  • Dopaminergic Neurons/metabolism*
  • Humans
  • Immobilization
  • Motor Activity/physiology*
  • Phylogeny
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • alpha-Synuclein/biosynthesis
  • alpha-Synuclein/genetics
  • beta-Synuclein/genetics
  • beta-Synuclein/metabolism*
  • gamma-Synuclein/metabolism*
PubMed: 22128150 Full text @ J. Biol. Chem.

α-Synuclein is strongly implicated in the pathogenesis of Parkinson2s 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) showed extensive phylogenetic conservation with respect to their human paralogues. A zebrafish α-synuclein orthologue was not found. Abundant 1.45kb sncb and 2.7kb 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 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.