Parkin counteracts symptoms in a Drosophila model of Parkinson's disease.
BACKGROUND
Parkinson's disease, a prevalent neurodegenerative disease, is characterized by the reduction of dopaminergic neurons resulting in the loss of motor control, resting tremor, the formation of neuronal inclusions and ultimately premature death. Two inherited forms of PD have been linked to mutations in the alpha-synuclein and parkin genes. The parkin protein functions as an ubiquitin ligase targeting specific proteins for degradation. Expression of human alpha-synuclein in Drosophila neurons recapitulates the loss of motor control, the development of neuronal inclusions, degeneration of dopaminergic neurons and the ommatidial array to provide an excellent genetic model of PD.


RESULTS
To investigate the role of parkin, we have generated transgenic Drosophila that conditionally express parkin under the control of the yeast UAS enhancer. While expression of parkin has little consequence, co-expression of parkin with alpha-synuclein in the dopaminergic neurons suppresses the alpha-synuclein-induced premature loss of climbing ability. In addition directed expression of parkin in the eye counteracts the alpha-synuclein-induced degeneration of the ommatidial array. These results show that parkin suppresses the PD-like symptoms observed in the alpha-synuclein-dependent Drosophila model of PD.


CONCLUSIONS
The highly conserved parkin E3 ubiquitin ligase can suppress the damaging effects of human alpha-synuclein. These results are consistent with a role for parkin in targeting alpha-synuclein to the proteasome. If this relationship is conserved in humans, this suggests that up-regulation of parkin should suppress alpha-synucleinopathic PD. The development of therapies that regulate parkin activity may be crucial in the treatment of PD.
Haywood
Annika F M
AF
Department of Biology, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, A1B 3X9, Canada. annikahaywood@warp.nfld.net
Staveley
Brian E
BE
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D017124:Conserved Sequence / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics* / Q000628:therapy; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D017386:Sequence Homology, Amino Acid; D015996:Survival Rate; D051843:Synucleins; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein
D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C487430:park protein, Drosophila; D004298:Dopamine