Anti-wrinkle ingredient: 'preventive potential' in Parkinson's disease

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Main Category: Parkinson's Disease
Also Included In: Neurology / Neuroscience;  Seniors / Aging;  Biology / Biochemistry
Article Date: 20 Aug 2013 - 0:00 PDT Current ratings for:
Anti-wrinkle ingredient: 'preventive potential' in Parkinson's disease

Scientists say they have discovered that a chemical used in anti-wrinkle cream has potential to prevent early-onset Parkinson's disease.

The findings could be used to develop drugs to prevent the cell death seen in the brains of people with Parkinson's disease, say the researchers from the University of California in San Francisco (UCSF).

The study, published in the journal Cell, analyzes the use of kinetin triphosphate (KTP) - a plant hormone that promotes cell division - as a way of increasing mutant PINK1 enzyme activity in the nerve cells to levels that are nearly normal.

According to the researchers, mutated PINK1 enzymes are directly responsible for many early-onset cases of Parkinson's disease.

Once PINK1 enzymes are mutated, this causes harm to the mitochondria - parts of the cells that are responsible for the conversion of food energy into alternative forms of energy used by cells.

When the performance of mitochondria is harmed, this can cause the death of nerve cells that produce dopamine within a brain region called the substantia nigra. This area of the brain controls movement, and lack of dopamine in this region is a cause of tremors, a common symptom of Parkinson's disease.

Dr. Kevan Shokat, a chemist at UCSF, says:

"In light of the fact that mutations in PINK1 produce Parkinson's disease in humans, the finding that kinetin can speed mutated PINK1 activity to near normal levels raises the possibility that kinetin may be used to treat these patients."

The researchers also discovered that when nerve cells with non-mutated PINK1 interacted with kinetin, enzyme activity also sped up ahead of normal levels.

The study authors say these findings may be relevant for the most common forms of Parkinson's disease, where PINK1 is not mutated.

A previous study revealed that when PINK1 showed similar overactivity in a fruit-fly model, the abnormal movement of Parkinson's disease caused by another defect slowed down. In this case, the defect was increased production of alpha-synuclein - a cause of some inherited types of Parkinson's disease.

For this most recent study, Dr. Shokat decided to target the substrate of PINK1 called ATP - a molecule that binds to the enzyme and triggers a fast chemical transformation. This chemical reaction encourages the activation of the Parkin enzyme.

The authors describe how both the PINK1 and Parkin enzymes work together to monitor the health of mitochondria, helping to trigger the repair or disposal of damaged mitochondria within the cells, encouraging cell survival.

Dr. Shokat says that although there have been many drugs developed that inhibit the activity of kinases, none has yet been marketed that directly boosts the activity of kinase.

He explains:

"Therapeutic approaches for enhancing the activity of PINK1 had not been considered, because scientists had not conceived of the idea of developing a new substrate for the enzyme."

"We found that a small molecule, called KTP, speeds chemical reactions catalyzed by PINK1 better than ATP, the natural substrate. That kind of better-than-natural response is essentially unheard of."

The researchers add that these findings may prompt the development of similar pharmaceutical treatments that could be used to tackle other diseases, such as cancer and diabetes.

Written by Honor Whiteman

Copyright: Medical News Today
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Parkinson's in men may be linked to testosterone decline

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Main Category: Parkinson's Disease
Also Included In: Neurology / Neuroscience;  Men's Health
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
Parkinson's in men may be linked to testosterone decline

Parkinson's disease in men may be linked to a sudden decline in testosterone, a study published in The Journal of Biological Chemistry suggests.

Researchers at Rush University Medical Center analyzed a number of male mice who had been castrated, dramatically decreasing their testosterone levels, and they found that the mice showed increased symptoms of Parkinson's disease.

Dr. Kalipada Pahan, professor of neurology at the university, explains, "While scientists use different toxins and a number of complex genetic approaches to model Parkinson's disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson's-like pathology and symptoms in male mice."

However, the researchers add that when the mice were given supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets, the symptoms of Parkinson's disease were reversed.

According to the researchers, in healthy males, testosterone is at its maximum levels in the mid-30s, gradually decreasing each year after then by around 1%. But they add that testosterone levels could also dramatically drop as a result of stress or other sudden life-changing events.

Dr. Kalipada Pahan adds:

"In men, testosterone levels are intimately coupled to many disease processes. Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson's disease."

Parkinson's disease is a disorder of the nervous system, which can affect how a person moves. Symptoms are progressive, usually beginning with small tremors in one hand.

According to statistics on Parkinson's from the Parkinson's Disease Foundation, there are thought to be around 1 million people in the US living with the disease, and around 60,000 Americans are diagnosed with Parkinson's every year. It is the world's second most common neurodegenerative disease.

The study authors say that from this research, it is apparent that understanding how Parkinson's disease works is important for developing drugs that protect the brain and halt progression.

They add the research suggests nitric oxide - a gas naturally produced in the body that communicates between cells - is an important molecule for developing these drugs.

Dr Pahan says:

"When nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase (iNOS), neurons start dying.

After castration, levels of iNOS and nitric oxide go up in the brain dramatically. Interestingly, castration does not cause Parkinson's-like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production."

He adds that further research is needed to see how testosterone levels in human males could be targeted in order to find a viable treatment.

Medical News Today recently reported on a Parkinson's discovery that yields the potential to 'protect' nerve cells.

Written by Honor Whiteman

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30 Jul. 2013. APA

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'Parkinson's in men may be linked to testosterone decline'

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Parkinson's discovery yields potential to 'protect' nerve cells

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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. APA

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'Parkinson's discovery yields potential to 'protect' nerve cells'

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Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy

Main Category: Parkinson's Disease
Article Date: 27 Jul 2013 - 0:00 PDT Current ratings for:
Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy

Biologists at The Scripps Research Institute (TSRI) have made a significant discovery that could lead to a new therapeutic strategy for Parkinson's disease.

The findings, recently published online ahead of print 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 has been unclear. But the TSRI researchers showed that parkin's loss sharply reduces the level of another protein that normally helps protect neurons from stress.

"We now have a good model for how parkin loss can lead to the deaths of neurons under stress," said TSRI Professor Steven I. Reed, who was senior author of the new study. "This also suggests a therapeutic strategy that might work against Parkinson's and other neurodegenerative diseases."

Genetic Clues

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 the characteristic motor symptoms, which include tremor, muscle rigidity and slowness of movements. These 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 are considered "sporadic" and are thought to be caused by a variable mix of factors including advanced age, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins. But between 5 and 15 percent of cases arise 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 age 40.

Parkin belongs to a family of enzymes called ubiquitin ligases, whose main function is to regulate the levels of other proteins. They do so principally by "tagging" their protein targets with ubiquitin molecules, thus marking them for disposal by roving protein-breakers in cells known as proteasomes. Because parkin is a ubiquitin ligase, researchers have assumed that its absence allows some other protein or proteins to evade proteasomal destruction and thus accumulate abnormally and harm neurons. But since 1998, when parkin mutations were first identified as a cause of early-onset Parkinson's, 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," Reed said.

Oxidative Stress

In 2005, Reed and his postdoctoral research associate (and wife) Susanna Ekholm-Reed decided to investigate a report that parkin associates with another ubiquitin ligase known as Fbw7. "We soon discovered that parkin regulates Fbw7 levels by tagging it with ubiquitin and thus targeting it for degradation by the proteasome," said Ekholm-Reed.

Loss of parkin, they found, leads to rises in Fbw7 levels, specifically for a form of the protein known as Fbw7ß. The scientists observed these elevated levels of Fbw7ß in embryonic mouse neurons from which parkin had been deleted, in transgenic mice that were born without the parkin gene, and even 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, so that Fbw7ß levels fall. Without the parkin-driven decrease in Fbw7ß levels, the neurons become more sensitive to this "oxidative stress" - so that more of them undergo a programmed self-destruction called apoptosis. Oxidative stress, to which dopamine-producing substantia nigra neurons may be particularly vulnerable, has long been considered a likely contributor to Parkinson's.

"We realized that there must be a downstream target of Fbw7ß that's important for neuronal survival during oxidative stress," said Ekholm-Reed.

A New Neuroprotective Strategy

The research slowed for a period due to a lack of funding. But then, in 2011, came a breakthrough. Other researchers who were investigating Fbw7's role in cancer reported 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," said Ekholm-Reed. The TSRI lab's experiments quickly confirmed the chain of events in neurons: parkin keeps levels of Fbw7ß under control, and Fbw7ß keeps levels of Mcl-1 under control. Full silencing of Mcl-1 leaves neurons extremely sensitive to oxidative stress.

Members of the team suspect that this is the principal explanation for how parkin mutations lead to Parkinson's disease. But perhaps more importantly, they believe that 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]," said Reed.

Finding such an Mcl-1-boosting compound, he added, is now a major focus of his laboratory's work.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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,” Susanna Ekholm-Reed, Matthew S. Goldberg, Michael G. Schlossmacher and Steven I. Reed, Published ahead of print 15 July 2013, doi: 10.1128/MCB.00535-13

Funding for the study was provided in part by the National Institutes of Health (NS059904 and CA078343).

Scripps Research Institute

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'Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy'

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