Genetic activation of parkin rescues TAF15-induced neurotoxicity in a Drosophila model of amyotrophic lateral sclerosis.

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that is characterized pathologically by the loss of motor neurons. Mutations in the TAF15 gene have been implicated in the pathogenesis of ALS. TATA-binding protein associated factor 15 (TAF15) accumulates as cytoplasmic aggregates in neuronal cells, the clearance of which may be a therapeutic strategy for ALS. However, the identification of a novel regulator for protection against a TAF15-induced proteinopathy and the exact pathogenic mechanism of TAF15-induced neurodegeneration remain to be elucidated. Here, we show that parkin directly binds to TAF15 and that parkin overexpression can suppress the defective phenotypes, including the life span and locomotive activity of a TAF15-induced proteinopathy. We also found that overexpression of parkin in neuronal cells leads to a reduction in TAF15 levels, because of the E3 ubiquitin ligase activity of parkin. Our study provides in vivo evidence supporting the use of parkin for neuroprotection in a TAF15-induced proteinopathy and offers new insights into the pathogenic mechanisms underlying TAF15-induced ALS.