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PMID:22128150

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Citation

Milanese, C, Sager, JJ, Bai, Q, Farrell, TC, Cannon, JR, Greenamyre, JT and Burton, EA (2012) Hypokinesia and reduced dopamine levels in zebrafish lacking β- and γ1-synucleins. J. Biol. Chem. 287:2971-83

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.

Links

PubMed PMC3270954 Online version:10.1074/jbc.M111.308312

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A0A2R8RP85

involved_in

GO:0008345: larval locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120216-10,ZFIN:ZDB-MRPHLNO-120216-9

P

Seeded From UniProt

complete

DANRE:A0A2R8RP85

involved_in

GO:0071542: dopaminergic neuron differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120216-10,ZFIN:ZDB-MRPHLNO-120216-7,ZFIN:ZDB-MRPHLNO-120216-8,ZFIN:ZDB-MRPHLNO-120216-9

P

Seeded From UniProt

complete

DANRE:Q502J6

involved_in

GO:0008345: larval locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120216-10,ZFIN:ZDB-MRPHLNO-120216-9

P

Seeded From UniProt

complete

DANRE:Q502J6

involved_in

GO:0071542: dopaminergic neuron differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120216-10,ZFIN:ZDB-MRPHLNO-120216-7,ZFIN:ZDB-MRPHLNO-120216-8,ZFIN:ZDB-MRPHLNO-120216-9

P

Seeded From UniProt

complete

DANRE:Q7SX92

involved_in

GO:0008345: larval locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120216-7,ZFIN:ZDB-MRPHLNO-120216-8

P

Seeded From UniProt

complete

DANRE:Q7SX92

involved_in

GO:0071542: dopaminergic neuron differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-120216-10,ZFIN:ZDB-MRPHLNO-120216-7,ZFIN:ZDB-MRPHLNO-120216-8,ZFIN:ZDB-MRPHLNO-120216-9

P

Seeded From UniProt

complete


See also

References

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