PINK1-mediated phosphorylation of Parkin boosts Parkin activity in Drosophila

PLoS Genet. 2014 Jun 5;10(6):e1004391. doi: 10.1371/journal.pgen.1004391. eCollection 2014 Jun.

Abstract

Two genes linked to early onset Parkinson's disease, PINK1 and Parkin, encode a protein kinase and a ubiquitin-ligase, respectively. Both enzymes have been suggested to support mitochondrial quality control. We have reported that Parkin is phosphorylated at Ser65 within the ubiquitin-like domain by PINK1 in mammalian cultured cells. However, it remains unclear whether Parkin phosphorylation is involved in mitochondrial maintenance and activity of dopaminergic neurons in vivo. Here, we examined the effects of Parkin phosphorylation in Drosophila, in which the phosphorylation residue is conserved at Ser94. Morphological changes of mitochondria caused by the ectopic expression of wild-type Parkin in muscle tissue and brain dopaminergic neurons disappeared in the absence of PINK1. In contrast, phosphomimetic Parkin accelerated mitochondrial fragmentation or aggregation and the degradation of mitochondrial proteins regardless of PINK1 activity, suggesting that the phosphorylation of Parkin boosts its ubiquitin-ligase activity. A non-phosphorylated form of Parkin fully rescued the muscular mitochondrial degeneration due to the loss of PINK1 activity, whereas the introduction of the non-phosphorylated Parkin mutant in Parkin-null flies led to the emergence of abnormally fused mitochondria in the muscle tissue. Manipulating the Parkin phosphorylation status affected spontaneous dopamine release in the nerve terminals of dopaminergic neurons, the survivability of dopaminergic neurons and flight activity. Our data reveal that Parkin phosphorylation regulates not only mitochondrial function but also the neuronal activity of dopaminergic neurons in vivo, suggesting that the appropriate regulation of Parkin phosphorylation is important for muscular and dopaminergic functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Drosophila Proteins / biosynthesis
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Electron Transport Complex I / metabolism
  • Membrane Proteins / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Muscle, Skeletal / innervation
  • Muscle, Skeletal / pathology
  • Parkinson Disease / genetics
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligases / biosynthesis
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Wings, Animal / innervation
  • Wings, Animal / pathology
  • rho GTP-Binding Proteins / metabolism

Substances

  • Drosophila Proteins
  • Marf protein, Drosophila
  • Membrane Proteins
  • Ubiquitin-Protein Ligases
  • PINK1 protein, Drosophila
  • Protein Serine-Threonine Kinases
  • Miro protein, Drosophila
  • rho GTP-Binding Proteins
  • park protein, Drosophila
  • Electron Transport Complex I

Grants and funding

This study was supported by the Takeda Science Foundation, the Life Science Foundation of Japan, the Daiichi-Sankyo Foundation for Life Science, and Otsuka Pharmaceutical. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.