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. 2004 Apr 16:5:14.
doi: 10.1186/1471-2202-5-14.

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

Annika F M Haywood  1 , Brian E Staveley
Affiliations

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

Annika F M Haywood et al. BMC Neurosci. .

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.

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Figures

Figure 1
Figure 1
Dipteran and mammalian parkin proteins are well conserved. (A) Schematic representation of the Drosophila melanogaster parkin transcription unit and its location in the genomic scaffolding region AE003593. (B) ClustalW alignment of the Drosophila melanogaster parkin with homologues from Anopheles gambiae, Rattus norvegicus, Mus musculus and Homo sapiens. Highlighted are the Ubiquitin-like Domain (UBL) (green box); the Unique Parkin Domain (UPD) (red box); RING1 and RING2 (blue boxes); In-Between Ring Domain (IRB) (black box). "*" and red lettering indicates amino acids that are identical in all sequences in the alignment. ":" and green lettering indicates conserved substitutions. "." and blue lettering indicates semi-conserved substitutions.
Figure 2
Figure 2
Expression of parkin suppresses α-synuclein-induced retinal degeneration. Flies that express α-synuclein with and without parkin were aged to 1 or 30 days old. They were fixed and embedded in epon. Tangential sections (0.5 μm thick) of the retina were cut, stained with toludine blue and examined by light microscopy. Panels A-C represent one-day-old flies and panels D-F represent thirty-day-old flies. Black arrows indicate degeneration of the ommatidial architecture. The genotypes are (A,D) w1118; UAS-α-synuclein/GMR-Gal4, (B,E) w1118; UAS-α-synuclein/GMR-Gal4; UAS-parkin1.1/+, and (C,F) w1118; UAS-α-synuclein/GMR-Gal4; UAS-parkin2.1/+. Scale bar is 15 μm.
Figure 3
Figure 3
Expression of α-synuclein with and without parkin does not affect the external morphology of the eye. Scanning electron microscopy of flies that express α-synuclein with and without parkin shows no change in their external morphology over thirty days. Panels A-C represent one-day-old flies and panels D-F represent thirty-day-old flies. The genotypes are (A,D) w1118; UAS-α-synuclein/GMR-Gal4, (B,E) w1118; UAS-α-synuclein/GMR-Gal4; UAS-parkin1.1/+, and (C,F) w1118; UAS-α-synuclein/GMR-Gal4; UAS-parkin2.1/+. Scale bar indicates 200 μm.
Figure 4
Figure 4
Expression of parkin does not affect climbing ability or life span. Panel A – Climbing ability of flies that express parkin does not differ from control flies. Genotypes are w1118; UAS-parkin1.1/Ddc-Gal4 (green open triangle), w1118; UAS-parkin2.1/Ddc-Gal4 (orange open square) and w1118; Ddc-Gal4/+ (black open circles). The error bars show the standard error of the mean of twenty trials at each point. Please note that the error bars are mostly within the symbols. B – The life span of flies that express parkin does not differ from the control. The genotypes are marked the same as in panel A. The mortality of flies was examined every two days.
Figure 5
Figure 5
Expression of parkin suppresses α-synuclein-induced loss of climbing ability. Panel A – Aged flies that express parkin and α-synuclein climb significantly better than flies that express α-synuclein (P < 0.001, one-way analysis of variance with supplementary Newman-Keuls test). Genotypes are w1118; UAS-α-synuclein/+; Ddc-Gal4/+ (green open square), w1118; UAS-α-synuclein/+; UAS-parkin1.1/Ddc-Gal4 (red open triangle), w1118; UAS-α-synuclein/+; UAS-parkin2.1/Ddc-Gal4 (blue upside down open triangle). The error bars show the standard error of the mean of twenty trials at each point. Please note that the error bars are mostly within the symbols. B – The life span of flies that express α-synuclein with and without parkin does not differ. The genotypes are marked the same as in panel A.
Figure 6
Figure 6
Model of parkin directed ubiquitination of α-synuclein. The parkin protein consists of two functionally distinct regions. The UBL/UPD region binds target proteins such as glycosylated α-synuclein. The RING-box (RING1-IBR-RING2) region recruits specific E2 ubiquitin conjugating enzymes, which add ubiquitin monomers to the target protein. In addition to substrate binding the UBL domain interacts with the proteasome. Ubiquitin tagged α-synuclein is directed to the proteasome and degraded into polypeptides and ubiquitin monomers. UBL – Ubiquitin-like Domain, UPD – Unique Parkin Domain, RING1 or 2 – Really Interesting New Gene finger 1 or 2 domain, IBR – In-Between Ring domain.
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