title: 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.
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: David T
authors.initials: DT
authors.lastname: Nguyen
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Olzomer
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Gin P
authors.initials: GP
authors.lastname: Poon
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cole
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Anita
authors.initials: A
authors.lastname: Puvanendran
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Brigitte R
authors.initials: BR
authors.lastname: Phillips
authors.affiliation: Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Australia, Sydney, NSW 2010, Australia. Electronic address: d.hesselson@garvan.org.au.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hesselson
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012402:Rotenone / Q000494:pharmacology; D000071456:Sequestosome-1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D042967:Electron Transport Complex I; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012402:Rotenone; D000071456:Sequestosome-1 Protein; D014268:Trifluoperazine; D029961:Zebrafish Proteins; D000099202:PTEN-Induced Putative Kinase; C099718:SQSTM1 protein, human; C570684:Tfeb protein, zebrafish; C558157:Pink1 protein, zebrafish
keywords: PINK1; Parkinson's disease; SQSTM1; TFEB; autophagy; chemical biology; rotenone; trifluoperazine; zebrafish