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Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila.

Parkin, an E3 ubiquitin ligase that degrades proteins with aberrant conformations, is associated with autosomal recessive juvenile Parkinsonism (AR-JP). The molecular basis of selective neuronal death in AR-JP is unknown. Here we show in an organismal system that panneuronal expression of Parkin substrate Pael-R causes age-dependent selective degeneration of Drosophila dopaminergic (DA) neurons. Coexpression of Parkin degrades Pael-R and suppresses its toxicity, whereas interfering with endogenous Drosophila Parkin function promotes Pael-R accumulation and augments its toxicity. Furthermore, overexpression of Parkin can mitigate alpha-Synuclein-induced neuritic pathology and suppress its toxicity. Our study implicates Parkin as a central player in the molecular pathway of Parkinson's disease (PD) and suggests that manipulating Parkin expression may provide a novel avenue of PD therapy.

Pubmed ID: 12670421

Authors

  • Yang Y
  • Nishimura I
  • Imai Y
  • Takahashi R
  • Lu B

Journal

Neuron

Publication Data

March 27, 2003

Associated Grants

None

Mesh Terms

  • Aging
  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Brain
  • Cell Death
  • Cells, Cultured
  • Dopamine
  • Drosophila
  • Drosophila Proteins
  • Gene Expression
  • Immunohistochemistry
  • Ligases
  • Nerve Tissue Proteins
  • Neurons
  • Parkinson Disease
  • RNA Interference
  • Receptors, Endothelin
  • Reverse Transcriptase Polymerase Chain Reaction
  • Synucleins
  • Ubiquitin-Protein Ligases
  • alpha-Synuclein