Examination of autophagy to ameliorate the toxicity of TDP-43, an Amyotrophic Lateral Sclerosis associated protein, using Caenorhabditis elegans.
Location
Poster #10
Department
Biology
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes motor neurons to progressively deteriorate leading to the loss of muscle function. On average, individuals with ALS live 2-5 years after diagnosis. A common characteristic of neurodegenerative disorders like ALS is the aggregation of disease proteins. In ALS, TAR DNA-binding protein 43 (TDP-43) accumulates in the cytosol of affected cells. Under normal physiological conditions, cells are able to clear aggregated proteins from the cytosol using a process called autophagy. When proteins are no longer functional, a phagophore engulfs the protein, forms a double membrane (autophagosome), and fuses with a lysosome which degrades the problematic protein using acidic lysosomal hydrolases. However, this protein clearance mechanism fails to remove TDP-43 in diseased cells. Understanding why this failure occurs may lead to future treatments that can improve cellular health. To investigate the role of autophagy on TDP-43 neurotoxicity, I will use the nematode C. elegans. Its short lifespan and well characterized nervous system make it a preferred model organism for neurological studies. In the Voisine lab, we have generated a transgenic line that pan-neuronally expressed human TDP-43 fused to a yellow fluorescent protein. Using well-established behavioral assays, we have demonstrated motor neuron dysfunction in our transgenic line, recapitulating aspects of human disease. To evaluate the role of autophagy in TDP-43 toxicity, I am conducting a genetic cross to introduce a deletion of rbg-1, which encodes a protein that regulates the formation and fusion of phagophores, into the TDP-43 transgenic lines. Once I confirm the presence of the rbg-1 deletion using molecular genotyping, I will conduct behavioral assays to assess motor neuron function. Results gained from this research will expand our knowledge of autophagy and protein clearance mechanisms for the removal of aggregated proteins in neurodegenerative diseases.
Faculty Sponsor
Cindy Voisine
Examination of autophagy to ameliorate the toxicity of TDP-43, an Amyotrophic Lateral Sclerosis associated protein, using Caenorhabditis elegans.
Poster #10
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes motor neurons to progressively deteriorate leading to the loss of muscle function. On average, individuals with ALS live 2-5 years after diagnosis. A common characteristic of neurodegenerative disorders like ALS is the aggregation of disease proteins. In ALS, TAR DNA-binding protein 43 (TDP-43) accumulates in the cytosol of affected cells. Under normal physiological conditions, cells are able to clear aggregated proteins from the cytosol using a process called autophagy. When proteins are no longer functional, a phagophore engulfs the protein, forms a double membrane (autophagosome), and fuses with a lysosome which degrades the problematic protein using acidic lysosomal hydrolases. However, this protein clearance mechanism fails to remove TDP-43 in diseased cells. Understanding why this failure occurs may lead to future treatments that can improve cellular health. To investigate the role of autophagy on TDP-43 neurotoxicity, I will use the nematode C. elegans. Its short lifespan and well characterized nervous system make it a preferred model organism for neurological studies. In the Voisine lab, we have generated a transgenic line that pan-neuronally expressed human TDP-43 fused to a yellow fluorescent protein. Using well-established behavioral assays, we have demonstrated motor neuron dysfunction in our transgenic line, recapitulating aspects of human disease. To evaluate the role of autophagy in TDP-43 toxicity, I am conducting a genetic cross to introduce a deletion of rbg-1, which encodes a protein that regulates the formation and fusion of phagophores, into the TDP-43 transgenic lines. Once I confirm the presence of the rbg-1 deletion using molecular genotyping, I will conduct behavioral assays to assess motor neuron function. Results gained from this research will expand our knowledge of autophagy and protein clearance mechanisms for the removal of aggregated proteins in neurodegenerative diseases.