Dataset Information

Parkin counteracts symptoms in a Drosophila model of Parkinson's disease.

ABSTRACT: 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. CONCLUSION: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.

SUBMITTER: Haywood AF

PROVIDER: S-EPMC419346 | biostudies-literature | 2004 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Parkin counteracts symptoms in a Drosophila model of Parkinson's disease.

Haywood Annika F M AF Staveley Brian E BE

BMC neuroscience 20040416

<h4>Background</h4>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 Droso ...[more]

PMID: 15090075

Similar Datasets

Project description:The dysfunction of the proteasome-ubiquitin system is commonly reported in several neurodegenerative diseases. Post mortem samples of brains of patients with Parkinson´s disease present cytoplasmic inclusions that are rich in proteins such as ubiquitin, Tau, and ?-synuclein. In Parkinson´s disease, a specific reduction of some of the proteasome subunits has also been reported. However, the specific role of the different proteasome subunits in dopaminergic neuron degeneration has not been thoroughly explored. In this work, we used the Gal4/UAS system to test fourteen Drosophila melanogaster RNAi lines from the Bloomington Drosophila Stock Center. Each of these lines targets a different proteasome subunit. To identify the strains that were able to induce neurodegeneration, we drove the expression of these lines to the eye and cataloged them as a function of the extent of neurodegeneration that they induced. The targeted proteasomal subunits are conserved in mammals and therefore may be relevant to study proteasome related diseases. The RNAi line among the regulatory subunits with the most penetrant phenotype targeted the proteasomal subunit Rpt2 and we decided to further characterize its phenotypes. Rpt2 knockdown in the Drosophila central nervous system reduced the activity of the proteasome, augmented the amount of insoluble ubiquitinated protein, and elicited motor and non-motor phenotypes that were similar to the ones found in Drosophila and other models for Parkinson's disease. When Rpt2 is silenced pan-neurally, third instar larvae have locomotion dysfunctions and die during pupation. Larval lethality was avoided using the Gal80-Gal4 system to induce the expression of the Rpt2 RNAi to dopaminergic neurons only after pupation. The reduction of Rpt2 in adult dopaminergic neurons causes reduced survival, hyperactivity, neurodegeneration, and sleep loss; probably recapitulating some of the sleep disorders that Parkinson's disease patients have before the appearance of locomotion disorders.

Dataset Information

Parkin counteracts symptoms in a Drosophila model of Parkinson's disease.

Publications

Parkin counteracts symptoms in a Drosophila model of Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets