C. elegans as a model organism for human disease

National Center For Advancing Translational Sciences

Investigators

Linked publications, trials & patents

Abstract

- Parkinson Disease (PD): In collaboration with Dr. D. Sibley (NINDS, NIH) the ADST laboratory has developed a 384-well qHTS laser cytometry-based screening assay for Parkinson’s Disease evaluating neurodegeneration of dopaminergic neurons in Caenorhabditis elegans (C. elegans) strains containing two different human PD-linked genes. Both strains express GFP in their dopaminergic neurons allowing for traceable fluorescence intensity as a measure of neuron health over time. A project update was reported at the March 2025 American Society for Pharmacology and Experimental Therapeutics Annual meeting (abstract No. 160193 by Martinez MA et al.). The goal of this project is to identify target proteins that when either knocked down by genetic approaches or inhibited by chemical agents halt or slow dopaminergic neuron degeneration caused by genetic mutations in genes critical to neuronal survival such as the leucine-rich repeat kinase 2 (LRRK2), or by environmental causes such as chemical exposure. A screening assay system based on the non-mammal C. elegans model organism was developed to identify agents with therapeutic potential. After identifying new molecules with this assay platform that slow or halt genetic or chemically triggered dopaminergic neurodegeneration, our goal is to determine their mechanism of action to inform new therapeutic strategies for PD. In this project, we are employing a C. elegans PD model based on human PD-linked gene mutations in the leucine-rich repeat kinase 2 (LRRK2). Using laser scanning cytometry methods, we have developed a 384-well quantitative high throughput screening (qHTS)-compatible C. elegans PD model system for evaluating libraries of siRNA or investigational agents and approved drugs for their ability to knockdown genes or inhibit protein functions that can suppress nematode neurodegeneration. - TANGO2 deficiency disorder: In a collaboration with Dr. Mackenzie’s laboratory (U. Rochester Medical Center) the ADST lab will develop a C. elegans qHTS assay to investigate the genotypic basis for the TANGO2 deficiency disorder (TDD) phenotype. TDD is an autosomal recessive neurodegenerative condition. C. elegans harbor two homologs of the TANGO2 gene, hrg-9 and hrg-10. Worms with biallelic pathogenic variants in these genes exhibit a strong behavioral phenotype that involves reduced brood size and low motility. We will exploit these characteristics to determine whether certain pharmacological compounds reverse or ameliorate the disease phenotype. The TDD C. elegans human model will be engineered to harbor one or more endogenously expressed fluorescent proteins to enable in vivo qHTS of drug and investigational agent chemical libraries. Lead compounds will be tested in follow-up experiments with the anticipation that they may also be beneficial for patients with TDD. Dr. Mackenzie’s laboratory generated a single knockout strain of hrg-10-/- mutants and acquired an hrg-9-/- knockout strain from the Caenorhabditis Genetics Center (CGC). His lab is in the process of generating a double knockout strain that also expresses a whole-body fluorescent reporter that will be provided to the ADST lab for the qHTS assay development component of the collaboration.