PUBLICATION

Embryonic Exposure to the Environmental Neurotoxin BMAA Negatively Impacts Early Neuronal Development and Progression of Neurodegeneration in the Sod1-G93R Zebrafish Model of Amyotrophic Lateral Sclerosis

Authors
Powers, S., Kwok, S., Lovejoy, E., Lavin, T., Sher, R.
ID
ZDB-PUB-170127-6
Date
2017
Source
Toxicological sciences : an official journal of the Society of Toxicology   157(1): 129-140 (Journal)
Registered Authors
Keywords
Amyotrophic Lateral Sclerosis, BMAA, Beta-methylamino-L-alanine, SOD1, climate change, harmful algal blooms
MeSH Terms
  • Amino Acids, Diamino/toxicity*
  • Amyotrophic Lateral Sclerosis/pathology*
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal*
  • Disease Progression
  • Environmental Exposure*
  • Genotype
  • Neurotoxins/toxicity*
  • Superoxide Dismutase-1/genetics
  • Superoxide Dismutase-1/metabolism*
  • Zebrafish/embryology*
  • Zebrafish/genetics
PubMed
28123103 Full text @ Toxicol. Sci.
CTD
28123103
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to progressive paralysis and death within 2-5 years after diagnosis. Sporadic cases (SALS) comprise ∼90% of cases with the remaining 10% familial (FALS) caused by mutations in ∼27 genes. The vast heterogeneity seen in age and location of disease onset, rate of progression, and duration of disease have been linked with genetic and environmental influences in both SALS and FALS cases. Increased ALS incidence clusters in Guam, southern France, and Maryland have been linked with exposure to Beta-methylamino-L-alanine (BMAA), a non-proteinogenic amino acid produced by cyanobacteria, dinoflaggelates, and diatoms. We embryonically exposed zebrafish, Danio rerio, (transgenically overexpressing a FALS-causing SOD1-G93R mutation) to BMAA to investigate early motor neuron outgrowth in larvae and endurance and fatigability in 5-month adults. SOD1-G93R zebrafish showed decreased embryonic nerve length with increased BMAA dose, a phenotypic change mirrored in 5-month performance measures of weaker swimming and increased fatigability. In contrast, transgenic fish overexpressing wild-type SOD1 were resistant to phenotypic changes, indicating a potential neuroprotective function of healthy SOD1. We show that the etiology of genetic ALS animal models can be influenced by environmental exposures, and that embryonic toxin exposures can result in changes to both early and adult measures. We demonstrate that zebrafish can be a robust model for investigating causes of ALS heterogeneity. Establishing these links between developmental and adult ALS-like symptoms in the zebrafish increases the power of this model for toxicological and drug screens.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping