Abstract
BackgroundParkinson'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 α-synuclein and parkin genes. The parkin protein functions as an ubiquitin ligase targeting specific proteins for degradation. Expression of human α-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.ResultsTo 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 α-synuclein in the dopaminergic neurons suppresses the α-synuclein-induced premature loss of climbing ability. In addition directed expression of parkin in the eye counteracts the α-synuclein-induced degeneration of the ommatidial array. These results show that parkin suppresses the PD-like symptoms observed in the α-synuclein-dependent Drosophila model of PD.ConclusionThe highly conserved parkin E3 ubiquitin ligase can suppress the damaging effects of human α-synuclein. These results are consistent with a role for parkin in targeting α-synuclein to the proteasome. If this relationship is conserved in humans, this suggests that up-regulation of parkin should suppress α-synucleinopathic PD. The development of therapies that regulate parkin activity may be crucial in the treatment of PD.
Highlights
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 premature death
Expression of parkin in dopaminergic neurons does not alter life span (Figure 4B). These results demonstrate that parkin expression in the dopaminergic neurons has little effect upon climbing ability or life span
The five characteristic domains of the parkin protein, the Ubiquitin- like Domain (UBL), Unique Parkin Domain (UPD), Really Interesting New Gene finger 1 (RING1) domain, InBetween Ring (IBR) domain and RING2 all show a high degree of similarity
Summary
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 premature death. Two inherited forms of PD have been linked to mutations in the α-synuclein and parkin genes. Expression of human α-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. Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by muscle tremors in stationary limbs, bradykinesia (slowed movement) and difficulty initiating and sustaining movements, and affects 1–2% of the population older than sixty years of age [1,2,3,4,5]. Mutations in a number of genes have been (page number not for citation purposes)
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