Publications

Abstract

Stimulating autophagy is a promising therapeutic strategy for slowing the progression of neurodegenerative disease. Neurons are insensitive to current approaches based on mTOR inhibition for activating autophagy and instead rely on the Parkinson's disease-associated proteins PINK1 and PARKIN to activate the autophagy-lysosomal pathway in response to mitochondrial damage. We developed a multifactorial zebrafish drug-screening platform combining Pink1 deficiency with an environmental toxin to compromise mitochondrial function and trigger dopaminergic neurone loss. Using a phenotypic screening strategy, we identified a series of piperazine phenothiazines, including trifluoperazine, which activated autophagy selectively in stressed zebrafish and human cells. We show that trifluoperazine acts downstream of, or parallel to, PINK1/PARKIN to stimulate Transcription Factor EB (TFEB) nuclear translocation and the expression of autophagy-lysosomal target genes. The cell-based and in vivo assays presented here will aid in the refinement of the trifluoperazine pharmacophore for the development of new stress-dependent autophagy activators.