TDP-43 mislocalization

TDP-43 is an RNA/DNA binding protein that plays important roles in RNA editing and metabolism. TDP-43 nuclear exclusion, cytoplasmic accumulation, and downregulation are pathologies seen across multiple neurodegenerative diseases, and these changes are closely associated with neurodegeneration. Deficits in nuclear-cytoplasmic trafficking (NCT) that arise in part from disruptions in the nuclear pore complex (NPC) contribute to TDP-43 mislocalization. How this occurs is still not well understood.  We have found that GDE2 loss in postmitotic neurons causes aberrant sustained activation of canonical Wnt signaling in neurons, and this is sufficient to cause TDP-43 mislocalization and dysfunction due to disruptions in NCT and NPC integrity. Notably, GDE2 loss and abnormal Wnt activation are observed in human iPSC-derived neurons from patients with ALS. Inhibition of Wnt signaling in iPSC-derived neurons from patients with ALS rescues TDP-43 dysfunction, suggesting that disruption of GDE2 regulation of Wnt contributes to TDP-43 abnormalities in disease contexts [Zhang et al.].

Current and future directions in the lab are focused on understanding how GDE2 loss activates canonical Wnt signaling, how Wnt activation in postmitotic neurons causes NPC and NCT abnormalities upstream of TDP-43 mislocalization, and examining if these pathways are disease-relevant. Parallel studies will explore roles for non-neuronal GDE expression that contribute to neuronal TDP-43 mislocalization.

Methodologies used in these studies include biochemistry, cell and molecular biology, mouse genetics, proteomics, primary cultures, human iPSCs, analysis of postmortem human tissue, viral work, and super-resolution imaging.