Abstract
Parkinson's disease (PD)-associated Pink1 and Parkin proteins are believed to function in a common pathway controlling mitochondrial clearance and trafficking. Glial cell line-derived neurotrophic factor (GDNF) and its signaling receptor Ret are neuroprotective in toxin-based animal models of PD. However, the mechanism by which GDNF/Ret protects cells from degenerating remains unclear. We investigated whether the Drosophila homolog of Ret can rescue Pink1 and park mutant phenotypes. We report that a signaling active version of Ret (Ret(MEN₂B) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants. Interestingly, corresponding phenotypes of park mutants were not rescued, suggesting that the phenotypes of Pink1 and park mutants have partially different origins. In human neuroblastoma cells, GDNF treatment rescues morphological defects of PINK1 knockdown, without inducing mitophagy or Parkin recruitment. GDNF also rescues bioenergetic deficits of PINK knockdown cells. Furthermore, overexpression of Ret(MEN₂B) significantly improves electron transport chain complex I function in Pink1 mutant Drosophila. These results provide a novel mechanism underlying Ret-mediated cell protection in a situation relevant for human PD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Apoptosis
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Autophagy
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Cell Line, Tumor
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Disease Models, Animal
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Dopamine / metabolism
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Drosophila Proteins / deficiency*
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Drosophila Proteins / genetics
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Drosophila Proteins / physiology*
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Drosophila melanogaster / genetics*
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Drosophila melanogaster / growth & development
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Electron Transport Complex I / physiology
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Genes, Lethal
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Glial Cell Line-Derived Neurotrophic Factor / pharmacology
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Humans
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Mitochondria, Muscle / ultrastructure*
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Muscular Atrophy / prevention & control*
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Neuroblastoma / pathology
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Neurons / ultrastructure
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Oxygen Consumption
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Parkinson Disease
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Phenotype
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Protein Kinases / deficiency
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Protein Kinases / genetics
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Protein Serine-Threonine Kinases / deficiency*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins c-ret / genetics
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Proto-Oncogene Proteins c-ret / physiology*
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Pupa
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Signal Transduction / physiology
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / genetics
Substances
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Drosophila Proteins
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Glial Cell Line-Derived Neurotrophic Factor
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Adenosine Triphosphate
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Ubiquitin-Protein Ligases
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Protein Kinases
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Proto-Oncogene Proteins c-ret
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Ret protein, Drosophila
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PINK1 protein, Drosophila
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PTEN-induced putative kinase
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Protein Serine-Threonine Kinases
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park protein, Drosophila
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Electron Transport Complex I
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Dopamine