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CANADA: Biologists Cure Parkinson’s In Fruit Flies By Deborah Inkpen Tue, 20 Apr 2004 While Memorial University biologists Dr. Brian Staveley and Annika Haywood didn't run yelling from their lab in St. John's when they made their amazing discovery, they did have a “eureka moment” thanks to the diminutive fruit fly, or Drosophila. Staveley and Haywood have cured Parkinson's disease in fruit flies. Their recent publication, Parkin Counteracts Symptoms in a Drosophila Model of Parkinson's Disease, is the result of three years intense research using fruit flies as the subjects for their research into the operation of cells. Parkinson's disease destroys the neurons in the part of the brain responsible for controlling the movement of muscles and affects more than one per cent of the population over 60 years of age. The disease results in the loss of motor control, resting tremor, the formation of neuronal inclusions and ultimately premature death. While attending Massey University in New Zealand, grad student Haywood read a paper in Nature describing how Dr. Mel Feany, Harvard Medical School, had made a model of Parkinson's disease in fruit flies by over-expressing a gene known to be involved in Parkinson's. “The fruit flies lost their climbing ability and neurons started to die off earlier. Other Parkinson's disease-like symptoms were found in the flies as well,” said Ms. Haywood. The article sparked her interest, she contacted Dr. Staveley and moved to Canada to begin work on genes that are altered in neuro-degenerative diseases like Parkinson's disease. “In our lab we use a combination of genetics, molecular biology, bioinformatics, behavioural tests and biochemistry to figure out how life and death works at the cellular level,” said Dr. Staveley. “Mostly, we are interested in genes that cause cells to survive.” While working together at Memorial, Dr. Staveley and Ms. Haywood started with a gene thought to be involved in the disease, parkin. The two then began to look for the parkin gene in fruit flies. They found the gene in the flies and proceed to make a transgenic Drosophila by taking the parkin gene and attaching it to another section of DNA and inserting this into Drosophila embryos. Then they crossed the transgenic flies with other flies and forced the expression of the parkin gene. “In Parkinson's disease, some of the genes seem to be involved in a pathway that gets rid of unwanted or damaged proteins. The gene parkin, a type of enzyme called ubiquitin ligase helps to put a little tag on specific proteins and says this protein needs to be degraded and gotten rid of,” said Ms. Haywood. “But if you lose the parkin gene there will be a build- up of proteins.” “It seems that in something that might cause a long slow death in a neuron is the build up over time of bad or damaged proteins,” said Dr. Staveley. “That may be one of the processes that lead to degeneration of neurons over a long period of time.” The team then asked the question, “If you have more parkin, will you get rid of more unwanted proteins?” The flies that had too much of the alpha-synuclein protein developed Parkinson's disease, but by adding more of the parkin gene, Parkinson's disease was suppressed. In explaining how the process of ridding the cell of the alpha-synuclein protein, Ms. Haywood said, “Part of the parkin gene will grab on to the alpha-synuclein protein and the other part will grab another protein called ubiquitin conjugating enzyme, which can tag the alpha-synuclein protein with a marker. So what parkin is really doing is mediating between the two, so the tag can be added. It is thought that the parkin gene might be attached to the `rubbish bin' of the cell, the proteasome and it will degrade the tagged protein. The proteins are degraded down to peptides and the tags are recycled.” “I often use the analogy that parkin acts like the guy that goes into the forest and puts the red X on trees and along comes the machinery and gets rid of the damaged or dead trees,” said Dr. Staveley. Their discovery may offer clues into finding a treatment of Parkinson's disease in humans. Dr. Staveley and Ms. Haywood hope medical researchers will take their work and develop a model curing it in humans. "These exciting results from a research group led by one of Memorial's younger scientific faculty members illustrate how traditional barriers between disciplines have fallen and how, as a result, fabulous new discoveries are possible by those with skills and knowledge derived from several disciplines,” said Dr. Robert Lucas, dean, Faculty of Science. “Dr. Staveley and his students, such as Ms. Haywood, have combined talents to take a major step towards understanding one of mankind's most debilitating diseases." The paper is published by BioMed Central, an independent on-line publishing house for peer-reviewed biomedical research. For more information on their paper and BioMed Central visit http://www.biomedcentral.com/home/ SOURCE: Memorial University of Newfoundland http://www.today.mun.ca/news.php?news_id=479 - - - parkin counteracts symptoms in a Drosophila model of Parkinson's disease Annika F M Haywood and Brian E Staveley BMC Neuroscience 2004, 5:14 (published 16 April 2004) Abstract (provisional) 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. SOURCE: BioMed Central http://www.biomedcentral.com/1471-2202/5/14/abstract - - - PubMed Abstract: parkin counteracts symptoms in a Drosophila model of Parkinson's disease. Haywood AF, Staveley BE. 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. PMID: 15090075 [PubMed - as supplied by publisher] SOURCE: PubMed http://www.biomedcentral.com/pubmed/15090075 - - - 1: Neuron. 2003 Mar 27;37(6):911-24. Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B. Laboratory of Developmental Neurobiology, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. 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. PMID: 12670421 [PubMed - indexed for MEDLINE] SOURCE: PubMed http://tinyurl.com/2nbyw Reference: Drosophila: a fly geneticist's swiss army knife http://www.geocities.com/murraycharters/010A.html * * * ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn