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Rescue of Pink1 Deficiency by Stress-Dependent Activation of Autophagy

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 may 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 neuron loss. Using a phenotypic screening strategy, we identified a series of piperazine phenothiazines, including trifluoperazine, which rescued Pink1 deficiency by activating 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 nuclear translocation and the expression of autophagy-lysosomal target genes. These data suggest that stress-dependent pharmacological reactivation of autophagy could prevent the loss of vulnerable neurons to slow neurodegeneration.

Type Journal
ISBN 2451-9456 (Electronic)
Authors Zhang, Y.; Nguyen, D. T.; Olzomer, E. M.; Poon, G. P.; Cole, N. J.; Puvanendran, A.; Phillips, B. R.; Hesselson, D.;
Publisher Name Cell Chemical Biology
Published Date 2017-02-01 00:00:00
Published Volume 24
Published Issue 4
Published Pages 471-480 e4
Status Published in-print
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/28366621
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/14039