TY  - JOUR
AU  - Klein, Pontus
AU  - Müller-Rischart, Anne Kathrin
AU  - Motori, Elisa
AU  - Schönbauer, Cornelia
AU  - Schnorrer, Frank
AU  - Winklhofer, Konstanze F
AU  - Klein, Rüdiger
TI  - Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants.
JO  - The EMBO journal
VL  - 33
IS  - 4
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-03594
SP  - 341-355
PY  - 2014
AB  - 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.
KW  - Adenosine Triphosphate: metabolism
KW  - Animals
KW  - Apoptosis
KW  - Autophagy
KW  - Cell Line, Tumor
KW  - Disease Models, Animal
KW  - Dopamine: metabolism
KW  - Drosophila Proteins: deficiency
KW  - Drosophila Proteins: genetics
KW  - Drosophila Proteins: physiology
KW  - Drosophila melanogaster: genetics
KW  - Drosophila melanogaster: growth & development
KW  - Electron Transport Complex I: physiology
KW  - Genes, Lethal
KW  - Glial Cell Line-Derived Neurotrophic Factor: pharmacology
KW  - Humans
KW  - Mitochondria, Muscle: ultrastructure
KW  - Muscular Atrophy: prevention & control
KW  - Neuroblastoma: pathology
KW  - Neurons: ultrastructure
KW  - Oxygen Consumption
KW  - Parkinson Disease
KW  - Phenotype
KW  - Protein Kinases: deficiency
KW  - Protein Kinases: genetics
KW  - Protein-Serine-Threonine Kinases: deficiency
KW  - Protein-Serine-Threonine Kinases: genetics
KW  - Protein-Serine-Threonine Kinases: physiology
KW  - Proto-Oncogene Proteins c-ret: genetics
KW  - Proto-Oncogene Proteins c-ret: physiology
KW  - Pupa
KW  - Signal Transduction: physiology
KW  - Ubiquitin-Protein Ligases: deficiency
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Drosophila Proteins (NLM Chemicals)
KW  - Glial Cell Line-Derived Neurotrophic Factor (NLM Chemicals)
KW  - Adenosine Triphosphate (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - Protein Kinases (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-ret (NLM Chemicals)
KW  - Ret protein, Drosophila (NLM Chemicals)
KW  - PINK1 protein, Drosophila (NLM Chemicals)
KW  - PTEN-induced putative kinase (NLM Chemicals)
KW  - Protein-Serine-Threonine Kinases (NLM Chemicals)
KW  - park protein, Drosophila (NLM Chemicals)
KW  - Electron Transport Complex I (NLM Chemicals)
KW  - Dopamine (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24473149
C2  - pmc:PMC3983680
DO  - DOI:10.1002/embj.201284290
UR  - https://pub.dzne.de/record/137272
ER  -