Compound Identified That Alleviates Parkinson’s Symptoms in Mice

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Researchers from Johns Hopkins and the National Cancer Institute (NCI) highlighted

a novel mechanism underlying Parkinson’s disease while simultaneously putting to

rest a previously held theory regarding progression of the disorder. They also

identified a compound that alleviates the disease’s symptoms in mice.


The investigators describe their work in a paper titled “Parthanatos mediates

AIMP2-activated age-dependent dopaminergic neuronal loss,” published online in

Nature Neuroscience.


“Not only were we able to identify the mechanism that could cause progressive cell

death in both inherited and noninherited forms of Parkinson’s, we found there were

already compounds in existence that can cross into the brain and block this from

happening,” said Valina Dawson, Ph.D., director of the stem cell biology and neuro-

regeneration programs at the Johns Hopkins University School of Medicine’s Institute

for Cell Engineering (ICE). “While there are still many things that need to happen

before we have a drug for clinical trials, we’ve taken some very promising first steps.”


Dr. Dawson and her husband, Ted Dawson, M.D., Ph.D., the director of ICE, have

collaborated for decades on studies of the molecular chain of events that lead to

Parkinson’s. One of their findings was that the function of an enzyme called parkin,

which malfunctions in the disease, is to tag a bevy of other proteins for destruction

by the cell’s recycling machinery. This means that nonfunctional parkin leads to the

buildup of its target proteins, and the Dawsons and others are exploring what roles

these proteins might play in the disease.


In the new study, the Dawsons collaborated with Debbie Swing and Lino Tessarollo of the

NCI to develop mice whose genes for a protein called AIMP2 could be switched into higher

performance. AIMP2 is one of the proteins normally tagged for destruction by parkin, so

the genetically modified mice enabled the research team to put aside the effects of

defective parkin and excesses of other proteins and look just at the consequences of

too much AIMP2.


They found that the mice developed symptoms similar to those of Parkinson’s as they aged.

The brain cells that make dopamine were dying. Since AIMP2 is known for its role in the

process of making new proteins, the researchers thought the cell death was caused by

problems with this process. But when graduate student Yunjong Lee looked at the efficiency

of protein-making in the affected mice, everything appeared normal.


Searching for an alternative explanation, Lee tested how cells with excess AIMP2 responded

to compounds blocking various paths to cell death and found that the AIMP2 was activating a

self-destruct pathway called parthanatos, discovered and named by the Dawsons years ago.


Lee found that AIMP2 triggered parthanatos by directly interacting with a protein called PARP1,

which was long thought to respond only to DNA damage and not to signals from other proteins.

Dr. Valina Dawson notes that AIMP2 is actually the second protein found to activate PARP1, but

the idea that PARP1 is only involved in detecting and responding to DNA damage is still firmly

entrenched in her field.


Since the Dawsons had been studying PARP1 for some time, they knew of compounds drug companies

had designed to block this enzyme. Such drugs are already in the process of being tested to

protect healthy cells during cancer treatment.

Parkinson’s Disease, Music and Mystery

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Parkinson’s Disease what effect does music have on its sufferers? What mysterious thing happens to us when we are exposed to or even participate in song?

When you sit back and listen to music, say Samuel Barber’s Adagio for strings, something happens.  What is that something?  Your heart rate synchronizes with the music, your mind quiets and your thoughts melt away into the melodies.  Your whole being transcends time and space and you float on the harmonies and gentle rhythm of the piece.  If you listen to say, Buddy Holly’s That’ll be the day, again, something happens.  Your pulse quickens, you begin tapping your feet to the rhythm, you break into a smile and memories of dancing and happy times flood into your consciousness.  Wherever you were, whatever you were doing, suddenly you are transported somewhere else and you feel the change.  If you have ever sung in a group or been part of a choir, you have experienced first- hand the surge of serotonin and the uplifting feeling that blending your voice with other voices all singing the same song brings.

So perhaps all this has something to do with why music therapy is so good for Parkinson’s.  Music is complex, music is dynamic, and it operates on many levels. It lifts the mood and lifts the spirit.  Parkinson’s is also a complex disease.  It is more than a tremor, stiffness and gait disturbance, more than a lack of dopamine in the substantia nigra, more than the alpha-synuclein, the mitochondria or cell surfaces or the chaperone molecules within the cells.  Music in all its complexity seems to harmonize with the complexity of Parkinson’s disease.  Taking what may be a depressed mood and turning it to happier thoughts and perhaps a lighter mood.

Music is one area that although it can be quantified into individual parts, is; as Aristotle commented “The whole is greater than the sum of its parts”.  It is a process.  Music’s effects on the human psyche and the variability of those effects defy explanation. Parkinson’s disease is also a process that has tended to defy explanation.  Reducing disease to cellular function can explain the cellular function or “mis-function” and the interactions between the cellular relationships.  It can show the how and what of the disease process, but it cannot tell us the why.  Parkinson’s is a dynamic system, with many effects changing from moment to moment.  Sometimes it is the “whole”; sometimes it is just a “part”.

Adding music therapy to treatment for Parkinson’s is bringing two dynamic systems (really many more) together to change the course of yet another.  Exactly how music calms the Parkinson’s beast has yet to be determined.  Yet more important is the fact that it is all a process, not an end point. The complexity of both dynamic systems interacting to bring the human state or the disease state to the edge of that creative process, to the edge of energy and potential and to stimulate new dynamic processes.

In complex systems, such as music and disease, there will always be missing information, unanswered questions.  Part of the process is knowing there are limits, there are things perhaps we cannot quantify or “know”.   Life is still, and hopefully will always be a mystery.  It is releasing and letting go, accepting those limits, and allowing “magic” to happen.  Music is magic…. and mystery; and what a sweet mystery it is!.

Investigational Gene Therapy Trial for Parkinson’s Disease

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A Phase I clinical trial for the treatment of Parkinson’s with Glial Cell Line Derived Neurotrophic Factor (GDNF) has completed the first procedure on the first patient at the University of California, San Francisco.  Krystof Bankiewicz, M.D., Ph.D. of UCSF and John D. Heiss, M.D., from the National Institutes for Neurological Diseases and Stroke are the joint chief investigators.  This trial will treat 24 patients in four cohorts that will receive varying doses of the GDNF. This is the first stage of testing for safety and dose response.

GDNF provides neuro regeneration and is expected to provide neuro-protective properties to strengthen dopamine producing cells in the brain.  It will be delivered directly to the putamen region of the brain, where dopamine is normally produced but is disrupted by Parkinson’s disease.   According to Dr. Bankiewicz “The success of gene therapy in patients requires accuracy in delivery.”  To achieve this accuracy, a program from the company MRI Interventions called “ClearPoint” is used.  “ClearPoint” is a system of technology to enable precise and exact placement of the gene therapy using MRI.  The infusion of the gene therapy to this very small and precise region of the brain is actually considered “minimally invasive” surgery.  The first patient received treatment on May 20th and there have been no safety issues.

This study is a collaboration between MRI Interventions, the manufacturers of the “ClearPoint” system for precise visualization, uniQure V.B. a Dutch Company that is providing the GDNF and UCSF.   It is sponsored by National Institutes of Health.  MRI Interventions “ClearPoint” system has received FDA approval.  UniQure specializes in human gene therapy treatments with potentially curative results.  They currently have one product that has been successful and are eager to bring new therapies to patients with severe disorders.

Additional note: This treatment of Parkinson’s with Glial Cell Line Derived Neurotrophic Factor (GDNF) was used in the UK in 2003 with remarkable results.  After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson’s Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [(18)F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function.

Nat Med. 2003 May;9(5):589-95. Epub 2003 Mar 31.Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Gill SS, Patel NK, Hotton GR, O’Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P. Source: Frenchay Hospital, Institute of Neurosciences, Bristol, UK.

Photo Credit:, , Wiki


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Turning Off and Turning On Parkinson Proteins   An amazing discovery was announced today that should lead to help for people with Parkinson’s disease soon.  Science has known how to turn off enzymes that affect various disorders, but turning them on has never been done.  Now a team of researchers from the Howard Hughes Medical Institute in San Francisco, California has done just that!  Through an extremely extensive search for the right molecule, they found it in an unexpected place:  a molecule long used as the basis for anti-wrinkle cream!

The gene PINK1, discovered in a familial strain of Parkinson’s, is known to help the mitochondria (energy suppliers) of neurons involved in Parkinson’s Disease.  PINK1 helps Parkin accumulate in the damaged mitochondria, but prevents further damage and helps the damaged cells to survive and not die.  If PINK1 could be increased, it might help keep those neurons functioning longer and prevent progression   In people who have mutations of PINK1Parkin is not found in the cells, and neuronal cell death follows.

The team wanted to find a way to strengthen PINK1 and started looking at the way that it is turned on by a particular molecule called ATP.  If they could understand how it was turned on, they might be able to find a less direct way to accomplish that task.  They started looking at molecules that were very similar to ATP, hoping to find one they could engineer to fit.  To their surprise, they found KTP, kinetin triphosphate, a very close relative of ATP that worked.  Not only did it turn on PINK1, but it also turned on the mutated forms of PINK1.

To verify that the addition of KTP did the same thing as ATP, they measured the amount of PINK1 activity and also the amount of Parkin that PINK1 brought to the mitochondrial surfaces as well as cell death.  Adding the precursor of KTP, kinetin, to the cells of both PINK1 and mutated PINK1 increased the activity, increased the Parkin and lead to less neuronal cell death.  Not only will this help people with the familial strain of Parkinson’s Disease, but also people who have the sporadic strain.

The group is now working to demonstrate the effectiveness of this discovery in animal models of Parkinson’s Disease.  There are several animal models, but the effects and results in animal models often are not the same as in humans.  However, since kinetin and KTP already have Food and Drug Administration approval and are not known to cause adverse reactions in humans, this should both speed up and simplify the process leading to clinical trials in humans.

Nicholas T. Hertz, Amandine Berthet, Martin L. Sos, Kurt S. Thorn, Al L. Burlingame, Ken Nakamura, Kevan M. Shokat. A Neo-Substrate that Amplifies Catalytic Activity of Parkinson’s-Disease-Related Kinase PINK1Cell, 2013; 154 (4): 737 DOI: 10.1016/j.cell.2013.07.030

Picture Credits: Melbourne Dermatology, Science Direct, Buy Me Beauty, and the above abstract.

Deep Brain Stimulation for Parkinson’s – Sooner Rather Than Later?

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A point of view article by four Canadian and UK neurologists who are very experienced with DEEP BRAIN STIMULATION was published in a recent issue of Annals of Neurology Journal.  They analyzed and reviewed results from current and long term studies of Deep Brain Stimulation in people with Parkinson’s and compared the results of Deep Brain Stimulation to standard medical treatment for Parkinson’s.  Present medical treatment for Parkinson’s consists of medical, surgical and supportive treatment.

Standard medical treatment for PARKINSON’S DISEASE has evolved considerably since the introduction of L-Dopa forty years ago and then the appearance of dopamine agonists.  New brain imaging techniques and greater understanding of the natural history of the disease have come a long way to help new therapies develop.  Advances in surgical technique plus the hardware for Deep Brain Stimulation have also become part of standard medical management.

Medical management has been divided into three areas:  Early Parkinson’s Disease, when it first affects motor function; Late stage PARKINSON’S DISEASE, where motor complications become apparent and surgical intervention.  There are standards for uncomplicated versus complicated and combinations of therapies to treat the motor problems and then complications.  But PARKINSON’S DISEASE also has non-motor symptoms, such as pain or depression, which these therapies are unable to satisfactorily address.  Surgical intervention has generally been reserved for those people for whom medical therapies are not sufficient or whose responses have been irregular and who have dyskinesias that cannot be resolved any other way.  These are often people in the later stages of PARKINSON’S DISEASE.

Deep Brain Stimulation now has a history of 12 to 14 years, since the Food and Drug Administration granted approval.  There are now some people who had Deep Brain Stimulation 10 years ago and are still showing clinically confirmed benefits.  Deep Brain Stimulation has both motor and non-motor benefits.  Deep Brain Stimulation reduces drug induced dyskinesias by as much as 60 to 80 per cent, while decreasing the amount of medication needed.  People who have had DEEP BRAIN STIMULATION demonstrate improvement on the Unified Parkinson’s Disease Rating Scale and also report improved quality of life.  While there are many qualities to recommend DEEP BRAIN STIMULATION, studies have shown that there are some side effects to be considered.  For instance, DEEP BRAIN STIMULATION of the subthalamic nucleus (STN) increased the long term response to L-Dopa medication, but it also worsened the short term response with the effect of mimicking early stage PARKINSON’S DISEASE.  DEEP BRAIN STIMULATION of the globus pallidus internus (GPi) was not as effective on motor symptoms as STN, but verbal fluency increased.  Both types of DEEP BRAIN STIMULATION report improvement in non-motor domains of pain, akathisia, cognitive function, emotion and improvement in the activities of daily living.  Many of the side effects are short term and resolve without problems.

Of course, there are other side effects of DEEP BRAIN STIMULATION, adverse events are always possible.  Surgery is always serious, and DEEP BRAIN STIMULATION surgery, done while the patient is awake, carries its share of potential problems.  The hardware must not only be properly placed, it must be monitored and adjusted from time to time and batteries need to be replaced. The safety profile of DEEP BRAIN STIMULATION has been so good that it is now recognized as an established therapy for PARKINSON’S DISEASE.  Given the improvement of both motor and non-motor symptoms, and the improved quality of life experience with the combination of surgical and medical treatment for PARKINSON’S DISEASE, the guidelines for consideration of DEEP BRAIN STIMULATION as a therapy may need reassessment.  Instead of waiting until later in the course of PARKINSON’S DISEASE to recommend DEEP BRAIN STIMULATION as a “rescue”, perhaps we should consider DEEP BRAIN STIMULATION earlier in order to “preserve” function.

Guidelines for DEEP BRAIN STIMULATION have generally been that the patient be responsive to L-Dopa therapy, be cognitively unimpaired and emotionally stable to undergo the surgery.  However, cognitive impairments, emotional debility and psychotic symptoms are part of PARKINSON’S DISEASE and often occur later in the disease, possibly ruling out DEEP BRAIN STIMULATION.  If DEEP BRAIN STIMULATION could be done before drug induced motor symptoms become problematic, before disease progression affects cognition and emotion, the patient could benefit from improved symptoms and improved quality of life…making it easier to remain working or socially engaged for a longer period of time.

DEEP BRAIN STIMULATION is certainly not a simple consideration.  There are many aspects to consider: social, familial, personal as well as medical.  Serious conversations with the medical providers, neurologists and neurosurgeon need to be undertaken.  Understanding the current situation and symptoms in relation to the course of the disease while weighing them against the benefits, side effects and adverse events of DEEP BRAIN STIMULATION should be considered.  While DEEP BRAIN STIMULATION now has a longer history and more people have benefited from it, at what point in the course of the disease it is appropriate to be offered needs to be re-evaluated.


deSouza, R.-M., Moro, E., Lang, A. E. and Schapira, A. H. V. (2013), Timing of deep brain stimulation in Parkinson disease: A need for reappraisal?. Ann Neurol., 73: 565–575. doi: 10.1002/ana.23890

Is There a Genetic Link Between Alzheimer’s and Parkinson’s?

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A newly released research paper by Valentina Moskvina, Ph.D., and associates from the Cardiff University School of Medicine in Wales, U.K. looked at both Alzheimer’s and Parkinson’s and did not find a common genetic link between them.  This was a statistical meta analysis of a prodigious number of studies that examined the genetics and pathology of patients with Parkinson’s or Alzheimer’s.  Data was analyzed three different ways and all three ways showed no genetic commonality.

Both diseases can appear to have some similarities,  both being progressive neurodegenerative diseases with onset later in life and the development of dementia in later stages of the disease.  The causes of these diseases are distinct, with Parkinson’s resulting from a lack of dopamine production in the substantia nigra causing a movement disorder.  In Alzheimer’s, it is the hippocampus and the entorhinal cortex that are affected with the depletion of acetylcholine resulting in learning and memory difficulties.  As the diseases progress, neurodegeneration progresses leading to dementia.  However many people with Parkinson’s never experience dementia or memory problems whereas Alzheimer’s is the cause of most dementia and memory problems.

Some genetic studies have suggested there might be genetic connections between the two diseases and there have been reports of Alzheimer’s pathology in Parkinson’s patients and Parkinson’s in Alzheimer’s patients.  Having one disease does not exclude the possibility of having the other, but does not mean that the two are connected.  One of  genome wide studies is finding new genes that are linked to either disease, and Dr. Moskvina has herself found new genes related to Alzheimer’s. This study has helped by showing that there is not a single gene that can give rise to either disease but there are some genetic regions that increase the risk for developing both diseases.

One important note about this study is that they did not include people with Lewy-Body Dementia, which shares some similarities with Alzheimer’s.  The researchers also noted there is always a possibility that more refined methods for research on genetics might become available in the future that could still find a common basis for these diseases.


Valentina Moskvina et al. Analysis of Genome-Wide Association Studies of Alzheimer Disease and of Parkinson Disease to Determine If These 2 Diseases Share a Common Genetic RiskJAMA Neurol., 2013 DOI:10.1001/jamaneurol.2013.448


Testosterone and it’s Possible Link to Parkinson’s in Men

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Sudden Decline in Testosterone May Cause Parkinson’s Disease Symptoms in Men

July 26, 2013 — The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson like symptoms in male mice. The findings were recently published in the Journal of Biological Chemistry.

One of the major roadblocks for discovering drugs against Parkinson’s disease* is the unavailability of a reliable animal model for this disease

“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,” said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush. “We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson’s pathology in male mice.”  “In men, testosterone levels are intimately coupled to many disease processes,” said Pahan. Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year. However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson’s disease. “Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson’s disease,” said Pahan.

Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson’s disease. Nitric oxide is an important molecule for our brain and the body.  “However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying,” said Pahan.  “This study has become more fascinating than we thought,” said Pahan. “After castration, levels of inducible nitric oxide synthase (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.”

“Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment,” said Pahan.

Other researchers at Rush involved in this study were Saurabh Khasnavis, PhD, student, Anamitra Ghosh, PhD, student, and Avik Roy, PhD, research assistant professor. This research was supported by a grant from the National Institutes of Health that received the highest score for its scientific merit in the particular cycle it was reviewed.

Parkinson’s is a slowly progressive disease that affects a small area of cells within the mid-brain known as the substantia nigra. Gradual degeneration of these cells causes a reduction in a vital chemical neurotransmitter, dopamine. The decrease in dopamine results in one or more of the classic signs of Parkinson’s disease that includes resting tremor on one side of the body; generalized slowness of movement; stiffness of limbs and gait or balance problems. The cause of the disease is unknown. Both environmental and genetic causes of the disease have been postulated.

*Parkinson’s disease affects about 1.2 million patients in the United States and Canada. Although 15 percent of patients are diagnosed before age 50, it is generally considered a disease that targets older adults, affecting one of every 100 persons over the age of 60. This disease appears to be slightly more common in men than women.


Story Source:

Rush University Medical Center. “Sudden decline in testosterone may cause Parkinson’s disease symptoms in men.” ScienceDaily, 26 Jul. 2013. Web. 8 Aug. 2013.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

  1. S. Khasnavis, A. Ghosh, A. Roy, K. Pahan. Castration Induces Parkinson Disease Pathologies in Young Male Mice via Inducible Nitric-oxide Synthase. Journal of Biological Chemistry, 2013; 288 (29): 20843 DOI: 10.1074/jbc.M112.443556


Scientists Find a Potential Cause of Parkinson’s Disease that points to a new Therapeutic Strategy

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Scientists Find a Potential Cause of Parkinson’s Disease 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 Fbw7β. The scientists observed these elevated levels of Fbw7β 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 Fbw7β for destruction, so that Fbw7β levels fall. Without the parkin-driven decrease in Fbw7β 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 Fbw7β 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 Fbw7β under control, and Fbw7β 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 Fbw7β-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 Fbw7β 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.

Authors of the study, “Parkin-Dependent Degradation of the F-box protein Fbw7 β Promotes Neuronal Survival in Response to Oxidative stress by Stabilizing Mcl-1,” include Matthew S. Goldberg of The University of Texas Southwestern Medical Center at Dallas and Michael G. Schlossmacher of the University of Ottawa. For more information about the paper, see

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

“We now have a good model for how parkin loss can lead to the deaths of neurons under stress,” says TSRI Professor Steven I. Reed.



The Scripps Research Institute. “Potential cause of Parkinson’s disease points to new therapeutic strategy.” ScienceDaily, 24 Jul. 2013. Web. 5 Aug. 2013.

American Society for Microbiology:  Parkin-Dependent Degradation of the F-box protein Fbw7β Promotes Neuronal Survival in response to oxidative stress by Stabilizing Mcl-1.  Published ahead of print 15 July 2013, doi: 10.1128/MCB.00535-13




Stem Cell Breakthrough

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Why don’t brain cells in Parkinson brains communicate better? A team of researchers in Aukland, New Zealand, have been working on that question for the last five years and have found some clues that may help both Parkinson’s and Alzheimer’s.
As new stem cells, immature cells, emerge in the brain, they need to grow into neurons and find their proper place in the brain and begin communicating with other neurons. In order to reach their destination, through a complex and tight inter cellular matrix, they become coated with a slippery substance, polysialic-acid-neutral cell adhesion molecule. This slippery substance reduces the friction so they can migrate and saves cell energy, but once the cell has found the right location, in order to be secured in position, the substance must be removed. Removal of the polysialic acid substance is also necessary for the dendrites (neural appendages) to connect with other neurons and begin to communicate. This process has been well known for many years, but what controls the process has been a mystery.
What happens to the slippery molecules when the cell no longer needs it? This team spent years trying many growth processes under various conditions before finding a clue. Actually, they found two clues. First, they learned that cells internalize the polysialic molecule dependent on cues received from collagen in the extra cellular matrix and gaseous molecules of nitrc oxide.
Then they found that if there is insulin in the matrix, the cell cannot absorb the slippery molecules. Parkinson’s and Alzheimer’s brains are less sensitive to insulin, so insulin is blocking the removal of the polysialic acid causing the cell to be unable to connect or communicate properly with other cells.
Dr. Maurice Curtis was the director of the study, and the experiments were done at the Centre for Brain Research laboratories in Aukland, New Zealand. Other researchers on the team were Dr. Hector Monzo, Distinqguished Professor Richard Fauli, Dr. Thomas Park, Dr. Birger Dieriks, Diedre Jansson and Professor Mike Dragunow. They have now begun testing new drug compounds to target the removal of polysialic acid from cells in hopes of improving the migration and connectivity of new stem cells in the brain.

Insulin and IGF1 modulate turnover of polysialylated neuronal cell adhesion molecule (PSA-NCAM) in a process involving specific extracellular matrix components
Hector J. Monzo1,2, Thomas I. H. Park1,3,Victor Birger Dieriks1,2, Deidre Jansson1,3,Richard L. M. Faull1,2, Mike Dragunow1,3,Maurice A. Curtis1,2,*
DOI: 10.1111/jnc.12363 Article Accepted for Publication

Video Games for Therapy – Nintendo Wii Benefits PD

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Video game aficionados have pretty much abandoned the Nintendo Wii….moving on to the next generation and looking for more action, excitement and better screen images.  Medical doctors, physical therapists and people with Parkinson’s are embracing the Wii…and its ability to improve balance and reduce falls.

Spending just 20 minutes a day playing three different Wii games along with workouts on treadmill and exercycle improved scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Tinnetti Balance Test. Dr. Antonella Peppe, a research professor at the Fondazione Sana Lucia in Rome did a pilot study with people with Parkinson’s and found the Wii balance board stimulated the central nervous system.  Improvements in rigidly, movement fine motor skills and energy levels were reported by all the participants  Dr. Peppe’s study confirms the results of other studies.

A different study was done at the Medical College of Georgia.Twenty people with Parkinson’s used the Wii for an hour, three times a week for four weeks.  They played bowling, tennis and boxing, all of which require balance, quick thinking, movement and exercise.  It not only improved all their motor scores, it improved energy levels and alleviated depression, too.  Dr. Ben Herz was the investigator.  He is program director for the school of occupational therapy at the Allied School of Health Sciences.  This study used people who had never had therapy for Parkinson’s,  so they had no preconceived notions of what therapy should be like.  Finding that it involved video games was a big surprise.  But in the end, it was so useful and made them feel so good that more than half of them bought the Wii to use at home.  Dr. Herz says he thinks game systems like the Wii are the future of occupational rehabilitation.

Medical College of Georgia (2008, April 7). Occupational Therapists Use Wii For Parkinson’s Study. ScienceDaily. Retrieved June 25, 2013, from­/releases/2008/04/080407074534.htm


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