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Modeling sporadic amyotrophic lateral sclerosis (sals) in zebrafish using environmental stressors

University of British Columbia

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of upper and lower motor neurons. The majority of ALS patients are considered of unknown origin, termed sporadic, and are largely assumed to arise from environmental insults. Despite this, research to date has been heavily focused on genetic models of the disease, which represent 10% of ALS cases. Research has made disappointing progress with elucidating disease initiating mechanisms and therapeutic translation in patients. Sporadic ALS (sALS) models may provide substantially more applicable insight into disease pathogenesis, however there is currently a lack of reliable and effective models. Zebrafish offer promising advantages to investigating ALS, with highly conserved biological processes to humans, including genes implicated in human neurodegenerative diseases. Further, they can be used for high throughput toxicity screening and are optically transparent as embryos to allow for high resolution imaging in vivo. Here, we investigate using zebrafish as a model for screening for motor neuron defects and hypothesize that exposure to particular environmental toxins can be used to induce ALS-like hallmarks in a zebrafish model. We find that the zebrafish is an efficient and effective model for screening motor neuron toxicity induced by neurotoxins and Bisphenol A (BPA) exposure has a clear dose-response effect on reduced motor neuron length and branching in embryos at 48 hours post fertilization (hpf). We provide evidence that motor axon length as a valid surrogate marker of motor neuron degeneration by confirming the conventional method of measuring the length from a sagittal view in defective motor axons represents their true length in 3 dimensions, and confirm that reduced motor axon length is associated with increased motor neuron death. Further, BPA exposure results in an ALS-like phenotype with reduced motor function at 24 and 48 hpf, reduced neuromuscular junction integrity and microglia activation in embryos at 48 hpf. Together, these results show that the zebrafish model is advantageous for screening toxin-induced motor neuron death and can be used as a valid model of sALS. This research can be extended to confirm ALS-associated neurotoxins and provide insight into pathogenic mechanisms of sALS.

Text

2017-08-16

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/62666

Interdisciplinary Studies

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/