Developing a cellular model of endogenous TDP-43 mislocalization


Translational Research

Poster Number: M222


Malaikah Wakadilo, 1. Youth Neurology Education and Research Program, 2. Massachusetts General Hospital

Background: Lou Gehrig’s disease, also known as ALS (Amyotrophic lateral sclerosis), is a progressive neurodegenerative disorder that is characterized by the loss of motor neurons that control skeletal muscle. While investigating these molecular mechanisms of ALS, a protein called TDP-43, an RNA and DNA binding protein, has been found to contribute to the progressive degeneration of motor neurons. This degeneration of motor neurons is due to TDP-43’s cytoplasmic mislocalization when motor neurons are placed in stressful conditions. The mislocalization then leads to the the formation of cytoplasmic aggregates that end up disrupting the neuron’s function.
Objectives: The aim is to develop a cellular model that displays the mislocalization of TDP-43 under stressful conditions
Results: The mislocalization model was configured by subjecting neural precursor cells to hyperosmotic stress using a compound called sorbitol. Immunofluorescence was then used to analyze how TDP-43 will react to the conditions in which the neural precursor cells have been placed in. As a result, as the sorbitol concentration increased, TDP-43 translocated from the nucleus to the cytoplasm.
Conclusion: Neural precursor cells under stressful conditions like hyperosmotic stress undergo TDP-43 cytoplasmic mislocalization. The extent of mislocalization is positively correlated with the degree of hyperosmotic stress, highlighting the impact of environmental conditions on TDP-43 dynamics.
*For a full list of Co-Authors please see poster