Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin.
Mutations in Pink1, a gene encoding a Ser/Thr kinase with a mitochondrial-targeting signal, are associated with Parkinson's disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism by which loss of Pink1 leads to neurodegeneration is not understood. Here we show that inhibition of Drosophila Pink1 (dPink1) function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons. The muscle pathology was preceded by mitochondrial enlargement and disintegration. These phenotypes could be rescued by the wild type but not the pathogenic C-terminal deleted form of human Pink1 (hPink1). The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1. Consistent with the genetic rescue results, we find that, in dPink1 RNA interference (RNAi) animals, the level of Parkin protein is significantly reduced. Together, these results implicate Pink1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila.
Yang
Yufeng
Y
Department of Pathology and Geriatric Research, Education and Clinical Center/Veterans Affairs Palo Alto Health Care System, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
Gehrke
Stephan
S
Imai
Yuzuru
Y
Huang
Zhinong
Z
Ouyang
Yingshi
Y
Wang
Ji-Wu
JW
Yang
Lichuan
L
Beal
M Flint
MF
Vogel
Hannes
H
Lu
Bingwei
B
D000818:Animals; D030801:Animals, Genetically Modified; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D008928:Mitochondria / Q000473:pathology*; D009132:Muscles / Q000473:pathology* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000473:pathology*; D010300:Parkinson Disease; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics*; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase
D029721:Drosophila Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C487430:park protein, Drosophila