Degree Name

Doctor of Philosophy


School of Biological Sciences


This study aimed to examine whether TDP-43 was capable of cell-to-cell spread in cell culture and in vivo using a Drosophila model, and if so whether the extracellular chaperone clusterin could prevent this spread. Additionally it was determined whether the expression of TDP-43 in a subset of Drosophila glial cells was sufficient to induce motor neuron defects and mortality, and whether the co-expression of clusterin was able to reduce this. The ability of clusterin to inhibit the aggregation of TDP-43 in vitro was also tested. Finally, thoracic spinal cord sections from ALS patients were examined via immunohistochemistry to determine if clusterin was a constituent of TDP-43 inclusions, which would be consistent with the two proteins interacting during ALS progression.

Results from both cell-culture and in vivo experiments demonstrated that TDP-43 was able to spread from the glial cells where it was originally expressed, to surrounding cells which included motor neurons. Taken together these results suggest that like SOD1, TDP-43 may have prion-like modes of transmission. In Drosophila larvae the co-expression of clusterin was able to reduce this spread. Expression of TDP-43 in the glial cells of Drosophila caused a significant reduction of lifespan and locomotor defects. While the co-expression of clusterin was not able to extend lifespan, it did result in the preservation of locomotor ability. This effect may have resulted from clusterin inhibiting TDP-43 aggregation, as it was found that clusterin could potently inhibit the aggregation of TDP-43286-331, a synthetic peptide corresponding to residues 286-331 of TDP-43. Finally, clusterin was identified in the cytoplasm of human motor neurons where it was found to be co-localised with aggregates containing TDP-43 in spinal cord tissue from ALS but not control patients. Collectively, the results suggest that clusterin may be involved in preventing the aggregation of TDP-43 in ALS, possibly by interacting with TDP-43 in the extracellular space during prion-like transmission between cells, or in the intracellular space following retrotranslocation of clusterin to the cytosol.



Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.