Investigating the role of the extracellular scl gene family in TDP-43-mediated neurotoxicity in C. elegans
Location
Golden Eagles
Start Date
2-5-2025 11:20 AM
Department
Biology
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of neurons controlling voluntary muscles, leading to muscle weakness, atrophy, and paralysis. In ALS, TAR DNA-binding protein 43 (TDP-43) forms abnormal aggregates in the cytoplasm of neurons, which may spread in a prion-like manner. Manipulating extracellular matrix components may lead to inhibition of this transmission. To investigate TDP-43-related neurotoxicity, we use the nematode C. elegans, which is amenable to genetic manipulation and has a simple nervous system. Ribosome profiling of young adult C. elegans expressing human TDP-43 pan-neuronally and wild-type animals identified differentially translated genes in the scl gene family, with some members upregulated over 50 fold in TDP-43 transgenic animals. These genes are associated with longevity, stress resistance, and are expressed in the extracellular matrix. Genetic crosses were performed to introduce specific scl gene deletions into the TDP-43 transgenic line. To evaluate the effects of these deletions on TDP-43 neurotoxicity, behavioral assays were conducted to monitor movement. In the thrashing assay, worms are placed in a buffer, and their body bends (thrashes) are counted over 30 seconds. We hypothesize that deleting scl gene members will alleviate motor neuron deficits, increasing the thrashing rate of TDP-43 animals. Wild-type C. elegans exhibit approximately 50 thrashes, while TDP-43 transgenic animals average 10 thrashes. Preliminary data indicates that deletion of the scl-9 gene significantly improves the thrashing rate of TDP-43 animals, doubling the average number of body bends. Given that scl genes share homology with human PI16, an inhibitor of matrix metalloproteinase-2 (MMP-2), which is critical for extracellular matrix (ECM) remodeling, our study suggests that scl gene deletions could impact TDP-43 transmission by altering the ECM environment. MMP-2 facilitates the breakdown of ECM components and the deletion of its inhibitor, PI16 orthologs, likely enhances MMP-2 activity. This increased activity alters the ECM potentially reducing transmission of TDP-43 and its associated toxicity. Thus, remodeling ECM components, such as those altered by scl gene expression, may offer a therapeutic approach to attenuate TDP-43 neurotoxicity.
Faculty Sponsor
Cindy Voisine
Investigating the role of the extracellular scl gene family in TDP-43-mediated neurotoxicity in C. elegans
Golden Eagles
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of neurons controlling voluntary muscles, leading to muscle weakness, atrophy, and paralysis. In ALS, TAR DNA-binding protein 43 (TDP-43) forms abnormal aggregates in the cytoplasm of neurons, which may spread in a prion-like manner. Manipulating extracellular matrix components may lead to inhibition of this transmission. To investigate TDP-43-related neurotoxicity, we use the nematode C. elegans, which is amenable to genetic manipulation and has a simple nervous system. Ribosome profiling of young adult C. elegans expressing human TDP-43 pan-neuronally and wild-type animals identified differentially translated genes in the scl gene family, with some members upregulated over 50 fold in TDP-43 transgenic animals. These genes are associated with longevity, stress resistance, and are expressed in the extracellular matrix. Genetic crosses were performed to introduce specific scl gene deletions into the TDP-43 transgenic line. To evaluate the effects of these deletions on TDP-43 neurotoxicity, behavioral assays were conducted to monitor movement. In the thrashing assay, worms are placed in a buffer, and their body bends (thrashes) are counted over 30 seconds. We hypothesize that deleting scl gene members will alleviate motor neuron deficits, increasing the thrashing rate of TDP-43 animals. Wild-type C. elegans exhibit approximately 50 thrashes, while TDP-43 transgenic animals average 10 thrashes. Preliminary data indicates that deletion of the scl-9 gene significantly improves the thrashing rate of TDP-43 animals, doubling the average number of body bends. Given that scl genes share homology with human PI16, an inhibitor of matrix metalloproteinase-2 (MMP-2), which is critical for extracellular matrix (ECM) remodeling, our study suggests that scl gene deletions could impact TDP-43 transmission by altering the ECM environment. MMP-2 facilitates the breakdown of ECM components and the deletion of its inhibitor, PI16 orthologs, likely enhances MMP-2 activity. This increased activity alters the ECM potentially reducing transmission of TDP-43 and its associated toxicity. Thus, remodeling ECM components, such as those altered by scl gene expression, may offer a therapeutic approach to attenuate TDP-43 neurotoxicity.