English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Journal Article

Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants

MPS-Authors
/persons/resource/persons78657

Schönbauer,  Cornelia
Schnorrer, Frank / Muscle Dynamics, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons78656

Schnorrer,  Frank
Schnorrer, Frank / Muscle Dynamics, Max Planck Institute of Biochemistry, Max Planck Society;

External Resource
No external resources are shared
Fulltext (public)

341.full.pdf
(Any fulltext), 4MB

Supplementary Material (public)
There is no public supplementary material available
Citation

Klein, P., Müller-Rischart, A. K., Motori, E., Schönbauer, C., Schnorrer, F., Winklhofer, K. F., et al. (2014). Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants. EMBO JOURNAL, 33(4), 341-355. doi:10.1002/embj.201284290.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0018-CF97-4
Abstract
Synopsis image Glial cell line derived neurotrophic factor (GDNF) improves survival in toxin-models of Parkinson's disease and is currently undergoing clinical development, however the protective mechanism is elusive. This study provides evidence that the GDNF receptor Ret rescues defects of a genetic Parkinson model and proposes a new mechanism-of-action. Active Ret overexpression rescues muscle degeneration and mitochondrial morphology in muscles and dopamine neurons in Pink1 mutant Drosophila. In human neuroblastoma cells, GDNF treatment rescues mitochondrial fragmentation caused by Pink1 knockdown. Ret signaling improves mitochondrial respiration and activity of complex I, providing a potential novel mechanism for the protective effect of GDNF/Ret. 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(MEN)(2B)) 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(MEN)(2B) 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.