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Monitoring Neuronal Survival via Longitudinal Fluorescence Microscopy
Published on: January 19, 2019
Evaluation of longevity enhancing compounds against transactive response DNA-binding protein-43 neuronal toxicity
Arnaud Tauffenberger1, Carl Julien, J Alex Parker
1CRCHUM, Montréal, Québec, Canada.
Abstract:
In simple systems, lifespan can be extended by various methods including dietary restriction, mutations in the insulin/insulin-like growth factor (IGF) pathway or mitochondria among other processes. It is widely held that the mechanisms that extend lifespan may be adapted for diminishing age-associated pathologies. We tested whether a number of compounds reported to extend lifespan in C. elegans could reduce age-dependent toxicity caused by mutant TAR DNA-binding protein-43 in C. elegans motor neurons. Only half of the compounds tested show protective properties against neurodegeneration, suggesting that extended lifespan is not a strong predictor for neuroprotective properties. We report here that resveratrol, rolipram, reserpine, trolox, propyl gallate, and ethosuximide protect against mutant TAR DNA-binding protein-43 neuronal toxicity. Finally, of all the compounds tested, only resveratrol required daf-16 and sir-2.1 for protection, and ethosuximide showed dependence on daf-16 for its activity.
Insights
Lifespan-extending compounds in C. elegans do not always protect against neurodegeneration. Some, like resveratrol and ethosuximide, show neuroprotective effects, with specific genetic dependencies.
Area of Science:
- Neuroscience
- Aging Research
- Genetics
Background:
- Lifespan extension in simple organisms involves pathways like dietary restriction and insulin/IGF signaling.
- Mechanisms promoting longevity are often presumed to mitigate age-related diseases.
- Neurodegenerative diseases, such as those linked to TAR DNA-binding protein-43 (TDP-43), represent significant age-associated pathologies.
Purpose of the Study:
- To investigate if compounds known to extend lifespan in C. elegans can protect against TDP-43-induced motor neuron toxicity.
- To determine the predictive value of lifespan extension for neuroprotective properties.
Main Methods:
- Utilized C. elegans as a model system to study neurodegeneration.
- Administered compounds previously reported to extend lifespan to assess their efficacy against TDP-43 toxicity.
- Analyzed neuroprotection and identified genetic dependencies (daf-16, sir-2.1) for specific compounds.
Main Results:
- Only half of the tested lifespan-extending compounds demonstrated neuroprotective effects against TDP-43 toxicity.
- Resveratrol, rolipram, reserpine, trolox, propyl gallate, and ethosuximide were identified as protective agents.
- Resveratrol's protection was dependent on daf-16 and sir-2.1, while ethosuximide's required daf-16.
Conclusions:
- Extended lifespan is not a reliable predictor of neuroprotective capacity against TDP-43-induced toxicity.
- Specific compounds exhibit neuroprotection, highlighting distinct mechanisms beyond general lifespan extension.
- The genetic pathways daf-16 and sir-2.1 play roles in mediating the neuroprotective effects of certain compounds.
