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.
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
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
Neuron
Date: Mar. 27, 2003
PubMed ID: 12670421
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