Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependant manner

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) is a progressive and ultimately fatal disease spectrum characterised by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Current disease modifying drugs have modest effects and novel therapies are sorely needed. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential of GSK3 inhibition to ameliorate TDP43-mediated toxicity in mammalian neurons. Expression of TDP-43 was found to both activate GSK3 and promote caspase mediated cleavage of TDP-43. Inhibition of GSK3 reduced the abundance of full-length and cleaved TDP-43 in rodent neurons expressing wild-type or disease-associated mutant TDP-43 and also ameliorated neurotoxicity. Our results suggest that TDP-43 turnover is promoted by GSK3 inhibition in a caspase-dependent manner, and that targeting GSK3 activity could have therapeutic value.