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

Neuron | Mar 27, 2003

http://www.ncbi.nlm.nih.gov/pubmed/12670421

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 RIS Download

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

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