UNDERSTANDING THE INFLUENCE OF TDP-43 LOSS-OF-FUNCTION ON NEUROTROPHIN SIGNALLING

TDP-43 is a DNA/RNA binding protein with a pathophysiological role in ALS and FTD, where it translocates out of the nucleus resulting in the loss of DNA/RNA regulatory functions. We found that TDP-43 knockdown, mutation and aggregation in neurons affects the proper splicing of the receptor Sortilin resulting in the generation of a soluble isoform. Sortilin functions as a trafficking receptor for neurotrophins and a co-receptor in pro-neurotrophin mediated death, and its soluble form results in reduced activity-dependent secretion of BDNF, and potentiation of pro-neurotrophin related neurodegeneration. Mice with hippocampal depletion of TDP-43 exhibit reduced synaptic plasticity which can be rescued by repairing the Sortilin defect. These effects were found in diseased iPS derived human neurons, and can be rescued by isogenic correction of TDP-43 mutations. This suggests that by reducing synapse critical activity-dependent BDNF secretion and enhancing pro-neurotrophin signalling, soluble Sortilin contributes to neurological diseases associated with TDP-43 dysfunction.

Author dc:creator

• TANN YONG YOU, JASON

• Neuroscience, TDP-43, Sortilin, Neurotrophins, Amyotrophic lateral sclerosis, Frontotemporal dementia