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

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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

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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

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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

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