Main Category: Parkinson's Disease
Also Included In: Neurology / Neuroscience
Article Date: 29 Jul 2013 - 0:00 PDT Current ratings for:
Parkinson's discovery yields potential to 'protect' nerve cells
Biologists at The Scripps Research Institute in California have made a significant discovery that could lead to a new therapeutic strategy for Parkinson's disease.
The findings, recently published online in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson's disease. Precisely how the loss of this enzyme leads to the deaths of neurons had been unclear.
The new report's senior author, Professor Steven Reed, said the Scripps team had now constructed a credible model in which parkin loss sharply reduces the level of another protein, Fbw7ß that normally helps protect neurons from oxidative stress.
Prof. Steven Reed said:
"This also suggests a therapeutic strategy that might work against Parkinson's and other neurodegenerative diseases"
Parkinson's is the world's second-most common neurodegenerative disease, affecting about one million people in the United States alone. The disease is usually diagnosed after the appearance of its characteristic tremor, muscle rigidity and slowness of movements.
These motor symptoms are caused by the loss of neurons in the substantia nigra, a brain region that normally supplies the neurotransmitter dopamine to other regions that regulate muscle movements.
Most cases of Parkinson's disease are "sporadic", caused by a variable mix of factors such aging, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins.
However, 5-15% of cases are genetic, arising specifically from inherited gene mutations. Among these, mutations to the parkin gene are relatively common. Patients who have no functional parkin gene typically develop Parkinson's-like symptoms before they turn 40 years of age.
Parkin is one of the ubiquitin ligase family of enzymes, whose main function is to regulate the levels of other proteins by "tagging" their protein targets with ubiquitin molecules, marking them for disposal by roving protein-breakers in cells known as proteasomes. Thus researchers assumed that absence of parkin allowed other protein to accumulate abnormally and harm neurons.
But since 1998, when parkin mutations were first identified as a cause of early-onset Parkinson's disease, consensus about the identity of this protein culprit has been elusive. "There have been a lot of theories, but no one has come up with a truly satisfactory answer," Prof. Steven Reed said.
In 2005, Prof. Reed and his wife, Susanna Ekholm-Reed, a postdoctoral research associate, decided to investigate a report that parkin associates with another ubiquitin ligase known as Fbw7.
They found that parkin regulates Fbw7 levels by tagging it with ubiquitin, targeting it for degradation by the proteasome. Therefore loss of parkin leads to rises in Fbw7 levels, specifically for a form of the protein known as Fbw7ß.
Steven and Suzanna observed elevated levels of Fbw7ß in embryonic mouse neurons from which parkin had been deleted, in transgenic mice born without the parkin gene, and, most importantly, in autopsied brain tissue from Parkinson's patients who had parkin mutations.
Subsequent experiments showed that when neurons are exposed to harmful molecules known as reactive oxygen species, parkin appears to work harder at tagging Fbw7ß for destruction. However, without the parkin-driven decrease in Fbw7ß levels, the neurons become more sensitive to this oxidative stress - so that more of them undergo programmed self-destruction (apoptosis). Dopamine-producing substantia nigra neurons may be particularly vulnerable to oxidative stress, which has long been suspected as a contributor to Parkinson's.
"We realized that there must be a downstream target of Fbw7ß that's important for neuronal survival during oxidative stress," Susanna Ekholm-Reed said. A lack of funding, however, slowed the research.
A new breakthrough came after other researchers investigating Fbw7's role in cancer reported in 2011 that it normally tags a cell-survival protein called Mcl-1 for destruction. The loss of Fbw7 leads to rises in Mcl-1, which in turn makes cells more resistant to apoptosis.
"We were very excited about that finding," Susanna Ekholm-Reed said.
The Scripps team followed up with a series of experiments that confirmed the key chain of events: parkin controls levels of Fbw7ß, which in turn keeps levels of Mcl-1 under control. Full silencing of Mcl-1 leaves neurons extremely sensitive to oxidative stress. The report suggests this is the principal explanation for how parkin mutations lead to Parkinson's disease.
The team also believe their discovery points to a broad new "neuroprotective" strategy: reducing the Fbw7ß-mediated destruction of Mcl-1 in neurons, which should make neurons more resistant to oxidative and other stresses.
"If we can find a way to inhibit Fbw7ß in a way that specifically raises Mcl-1 levels, we might be able to prevent the progressive neuronal loss that's seen not only in Parkinson's but also in other major neurological diseases, such as Huntington's disease and ALS [amyotrophic lateral sclerosis]," Prof. Steven Reed said.
Written by: Nick Valentine
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today Visit our parkinson's disease section for the latest news on this subject. “Parkin-dependent degradation of the F-box protein Fbw7 ß promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1,” Ekholm-Reed S, Goldberg MS, Schlossmacher MG and Reed SI. Published ahead of print 15 July 2013. DOI: 10.1128/MCB.00535-13. Please use one of the following formats to cite this article in your essay, paper or report:
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29 Jul. 2013.
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'Parkinson's discovery yields potential to 'protect' nerve cells'
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