[
International Worm Meeting,
2021]
Optogenetic tools have revolutionized the study of neuronal circuits in Caenorhabditis elegans. The expression of light-sensitive ion channels or pumps under specific promotors allows researchers to modify the behavior of excitable cells. Several optogenetic systems have been developed to spatially and temporally photoactivate light-sensitive actuators in C. elegans. Nevertheless, their high costs and low flexibility have limited access to optogenetics for a broad public. Here, we developed an inexpensive, easy-to-build and highly adjustable optogenetics device for use with different microscopes and wormtrackers, called the OptoArm. The OptoArm allows for single-and multiple-worm illumination during imaging and is adaptable in terms of light intensity, lighting profiles and light-color. We demonstrate the system's versatility by performing multi-parameter behavioral analysis upon cholinergic and GABAergic stimulation. Furthermore, we leveraged the OptoArm's power in a population-based study to dissect the contributions of motor circuit cells to age-related motility decline. We discovered that the functional decline of cholinergic neurons corresponds with motor decline, while GABAergic neurons and muscle cells appear relatively age-resilient. This would suggest a rate-limiting, cell type-specific vulnerability to ageing, which may underlie neuronal circuit aging.
[
International Worm Meeting,
2021]
Protein toxicity is thought to underlie several, yet incurable, age-related neurodegenerative diseases, including Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS). TDP-43 aggregation is the major pathological hallmark of ALS and present in 97% of all cases, suggesting that TDP-43 contributes to in the disease mechanism. How protein toxicity triggers cell-and physical dysfunction and leads to degeneration is still not understood. This project aims to find disease mechanisms and uncover targets to suppress ALS-related TDP-43 toxicity. For this aim, a combination of genetic- and phenotypic screens in a Caenorhabditis elegans model for disease are being used. We make use of a C.elegans strain with overexpressed human TDP-43, which shows several cellular- and behavioral ALS disease phenotypes, including age-related motor impairment is used as a model. We performed a genetic screen, which identified 22 mutant animals that show a suppression of this impairment. The strongest suppressor mutant, called MOTT-22 (Modifier of TDP-43 Toxicity 22), was selected for further experiments. We are currently verifying and characterizing a candidate gene that may be responsible for the suppression of motor impairment in MOTT-22. After finding a candidate gene for MOTT-22, gene functions in the cell will be studied to find new mechanisms involved in protein toxicity.