ZFIN ID: ZDB-PUB-170404-13
Rescue of Pink1 Deficiency by Stress-Dependent Activation of Autophagy
Zhang, Y., Nguyen, D.T., Olzomer, E.M., Poon, G.P., Cole, N.J., Puvanendran, A., Phillips, B.R., Hesselson, D.
Date: 2017
Source: Cell chemical biology   24(4): 471-480.e4 (Journal)
Registered Authors: Cole, Nicholas, Hesselson, Daniel, Zhang, Yuxi
Keywords: PINK1, Parkinson's disease, SQSTM1, TFEB, autophagy, chemical biology, rotenone, trifluoperazine, zebrafish
MeSH Terms:
  • Animals
  • Autophagy*/drug effects
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
  • Behavior, Animal/drug effects
  • Cell Line, Tumor
  • Disease Models, Animal
  • Electron Transport Complex I/metabolism
  • Humans
  • Membrane Potential, Mitochondrial/drug effects
  • Mitochondria/drug effects
  • Mitochondria/metabolism
  • Neurons/metabolism
  • Parkinson Disease/metabolism
  • Parkinson Disease/pathology*
  • Protein Kinases/chemistry
  • Protein Kinases/genetics
  • Protein Kinases/metabolism
  • Protein Serine-Threonine Kinases/deficiency
  • Protein Serine-Threonine Kinases/genetics*
  • Protein Serine-Threonine Kinases/metabolism
  • RNA Interference
  • Rotenone/pharmacology
  • Sequestosome-1 Protein/antagonists & inhibitors
  • Sequestosome-1 Protein/genetics
  • Sequestosome-1 Protein/metabolism
  • Trifluoperazine/pharmacology
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 28366621 Full text @ Cell Chem Biol
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.