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

TL;DR

Inhibiting GSK3 reduces TDP-43 toxicity in neurons, offering a potential new treatment for ALS and FTD.

Contribution

This study shows that inhibiting GSK3 reduces TDP-43 toxicity in mammalian neurons via caspase-dependent mechanisms.

Findings

GSK3 inhibition reduces full-length and cleaved TDP-43 in neurons.

GSK3 inhibition ameliorates TDP-43-mediated neurotoxicity in a caspase-dependent manner.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive and ultimately fatal diseases 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 TDP-43-mediated toxicity in mammalian neurons. Expression of TDP-43 both activated GSK3 and promoted caspase mediated cleavage of TDP-43. Conversely, GSK3 inhibition reduced the abundance of full-length and cleaved TDP-43 in neurons expressing wild-type or disease-associated mutant TDP-43, ultimately ameliorating neurotoxicity. Our results suggest that TDP-43 turnover is promoted by GSK3 inhibition in a caspase-dependent manner, and that targeting GSK3 activity has therapeutic value.

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