Accepting PhD Students

PhD projects

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.