PUBLICATION

Neurotoxicity of the Parkinson's Disease-Associated Pesticide Ziram Is Synuclein-Dependent in Zebrafish Embryos

Authors

Lulla, A., Barnhill, L., Bitan, G., Ivanova, M.I., Nguyen, B., O'Donnell, K., Stahl, M.C., Yamashiro, C., Klärner, F.G., Schrader, T., Sagasti, A., Bronstein, J.M.

ID

ZDB-PUB-160616-8

Date

2016

Source

Environmental health perspectives 124(11): 1766-1775 (Journal)

Registered Authors

Barnhill, Lisa, Bronstein, Jeff, Sagasti, Alvaro

Keywords

none

MeSH Terms

Zebrafish/embryology*
Neurotoxins/toxicity*
Ziram/toxicity*
Parkinson Disease/etiology*
Animals
Behavior, Animal/drug effects
Embryo, Nonmammalian/drug effects*
Embryo, Nonmammalian/metabolism
Dopaminergic Neurons/drug effects*
Dopaminergic Neurons/metabolism
Synucleins/genetics
Synucleins/metabolism
Synucleins/physiology*

(all 13)

PubMed

27301718 Full text @ Environ. Health Perspect.

Abstract

Exposure to the commonly used dithiocarbamate (DTC) pesticide ziram is associated with an increased risk of developing Parkinson's disease (PD), although the mechanisms of toxicity are not completely understood. In this study, we utilized zebrafish (ZF) embryos to study the mechanisms of ziram's neurotoxicity in vivo. Nanomolar concentrations of ziram caused selective loss of dopaminergic (DA) neurons and impaired swimming behavior. Since ziram increases α-synuclein (α-syn) concentrations in rat primary neuronal cultures, we investigated the effect of ziram on ZF γ-synuclein 1 (γ1). ZF express 3 synuclein isoforms and ZF γ1 appears to be a functional homologue of α-syn. We found that recombinant ZF γ1 formed fibrils in vitro and overexpression of ZF γ1 in ZF embryos led to the formation of neuronal aggregates and neurotoxicity similarly to α-syn. Importantly, knockdown of ZF γ1 with morpholinos or disruption of oligomers with the molecular tweezer CLR01 prevented ziram's DA toxicity. These data demonstrate that ziram is selectively toxic to DA neurons in vivo and this toxicity is synuclein-dependent. These findings have important implications for understanding the mechanisms by which pesticides may cause PD.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by environment: ziram, chemical treatment by environment: apomorphine	Days 7-13	swimming behavior increased occurrence, abnormal	Fig. 2
AB	chemical treatment by environment: ziram, chemical treatment by environment: apomorphine	Days 7-13	swimming behavior process quality, abnormal	Fig. 2
AB	chemical treatment by environment: apomorphine	Days 7-13	swimming behavior increased occurrence, abnormal	Fig. 2
AB	chemical treatment by environment: apomorphine	Days 7-13	swimming behavior process quality, abnormal	Fig. 2
AB	chemical treatment by environment: haloperidol	Days 7-13	swimming behavior decreased occurrence, abnormal	Fig. 2
AB	chemical treatment by environment: haloperidol	Days 7-13	swimming behavior process quality, abnormal	Fig. 2
AB	chemical treatment by environment: ziram	Day 5	whole organism sncgb expression decreased amount, abnormal	Fig. 5
AB	chemical treatment by environment: ziram	Day 5	whole organism ab3-th labeling decreased amount, abnormal	Fig. S3
AB	chemical treatment by environment: ziram	Days 7-13	swimming behavior decreased occurrence, abnormal	Fig. 2
AB	chemical treatment by environment: ziram	Days 7-13	swimming behavior process quality, abnormal	Fig. 2

1 - 10 of 18

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
pku2Et	Et(gata2a:EGFP)	Transgenic Insertion
zf154Tg	Tg(isl1a:GAL4-VP16,UAS:EGFP)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
Parkinson's disease			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
sncgb	MO3-sncgb	MRPHLNO

Fish

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GAL4	EFG	GAL4
GFP	EFG	GFP

Mapping

Lulla et al., 2016 ZDB-PUB-160616-8 PMID:27301718

Neurotoxicity of the Parkinson's Disease-Associated Pesticide Ziram Is Synuclein-Dependent in Zebrafish Embryos

Lulla et al., 2016

ZDB-PUB-160616-8
PMID:27301718