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.
Yang
Yufeng
Y
Laboratory of Developmental Neurobiology, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Nishimura
Isao
I
Imai
Yuzuru
Y
Takahashi
Ryosuke
R
Lu
Bingwei
B
D000375:Aging; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D004298:Dopamine / Q000502:physiology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D015870:Gene Expression; D007150:Immunohistochemistry; D008025:Ligases / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000633:toxicity; D009474:Neurons / Q000502:physiology*; D010300:Parkinson Disease; D034622:RNA Interference; D017466:Receptors, Endothelin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein
D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; C473488:Pael-R protein, Drosophila; D017466:Receptors, Endothelin; D051843:Synucleins; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases; D004298:Dopamine