SCF‐Slimb is critical for Glycogen synthase kinase‐3β‐mediated suppression of TAF15‐induced neurotoxicity in Drosophila

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterized pathologically by motor neuron degeneration and associated with aggregation of RNA‐binding proteins. TATA‐binding protein‐associated factor 15 (TAF15) accumulates as cytoplasmic aggregates in neuronal cells, and clearance of these aggregates is considered a potential therapeutic strategy for ALS. However, the exact pathogenic mechanism of TAF15‐induced neurotoxicity remains to be elucidated. Glycogen synthase kinase‐3 (GSK‐3) plays a critical role in the protection of ALS pathology. In the present study, we use a transgenic fly model over‐expressing human TAF15 to study the protective effects of Shaggy/GSK3β on TAF15‐induced neuronal toxicity in Drosophila brain. Transgenic flies were examined for locomotor activity and lithium treatment. The expression level and solubility of TAF15 were assessed with western blotting, whereas immunohistochemistry was used to assess TAF15 aggregation in Drosophila brain. We have revealed that Shaggy/GSK3β was abnormally activated in neurons of TAF15‐expressing flies and its inhibition can suppress the defective phenotypes, thereby preventing retinal degeneration and locomotive activity caused by TAF15. We have also found that Shaggy/GSK3β inhibition in neuronal cells leads to a reduction in TAF15 levels. Indeed, the F‐box proteins Slimb and archipelago genetically interact with TAF15 and control TAF15 protein level in Drosophila. Importantly, SCFslimb is a critical regulator for Shaggy/GSK3β‐mediated suppression of TAF15‐induced toxicity in Drosophila. The present study has provided an in vivo evidence supporting the molecular mechanism of GSK3β inhibition for protection against TAF15‐linked proteinopathies. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder characterized pathologically by motor neuron degeneration and associated with aggregation of RNA‐binding proteins. TATA‐binding protein‐associated factor 15 (TAF15) accumulates as cytoplasmic aggregates in neuronal cells, and clearance of these aggregates is considered a potential therapeutic strategy for ALS. In this study, we show in TAF15‐expressing Drosophila models that Shaggy/GSK3β inhibition in neuronal cells leads to a reduction in TAF15 levels, and SCFslimb is a critical regulator for Shaggy/GSK3β‐mediated suppression of TAF15‐induced toxicity in Drosophila. This presents in vivo evidence supporting GSK3β inhibition as an agent in neuroprotection ag