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  • Biology
    University of York
    Wentworth Way
    YO10 5DD

Phone: (01904) 328729

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Dr. Han-Jou Chen

Lecturer in Neuroscience

PhD opportunities

Dimerization and RNA-binding dynamics of TDP-43 during stress responses in neurons. RNA-binding proteins (RBPs) are known to play an important role in neurons, where they are involved heavily in maintaining normal cell function. Mis-behavior of those proteins can be caused by cellular stress or dysregulation of protein homeostasis, which leads to protein aggregation with consequent damage to neurons. One such RBP is TDP-43, which has a high propensity to form aggregates. These aggregates are observed in neurons of ageing and neurodegenerative conditions. Under basal conditions, TDP-43 shuttles between nucleus and cytoplasm transporting its targeted RNA molecules to neuronal extensions for further processing. When the cells are stressed, TDP-43 brings target RNAs into an organelle called a stress granule where they are protected from degradation during stress. Stress granules are dynamic structures that are quickly dissembled when the stress is resolved. This mechanism ensures a rapid recovery of protein production for neurons recovering from stress. Several studies have indicated that interaction with RNA has an impact on the clustering properties of TDP-43. However, the nature of the TDP-43 cluster and the mechanism involved in clustering remain largely unclear. This project will address the following key questions: • What mechanisms are involved in the basal activity of TDP-43? • What are the molecular and cellular processes that contribute to TDP-43 aggregation? • How do different functional domains of TDP-43 contribute to the stress response and recovery period? The student will use wide range of biochemical and biophysical analyses to characterize TDP-43 solubility, self-association and structural changes under different conditions. These will be complemented with cell culturebased studies where the dynamics of TDP-43 protein movement will be monitored using live-cell imaging. The student will also use primary neurons and in vivo models to validate the findings.

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