A Sweet Approach to a Treatment for PARKINSON’S DISEASE

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A Sweet Approach to a Treatment for PARKINSON’S DISEASE

A team of Israeli researchers from Tel Aviv University presented their original evidence on their research with the artificial sweetener mannitol at the Drosophila Conference last year and published the results in the Journal of Biological Chemistry.  The results were “sweet”!

Mannitol is an artificial sweetener found in many sugar-free chewing gum and candy productsA Sweet Approach to a Treatment for PARKINSON’S DISEASE.  It is a sugar alcohol derived from many natural plant sources.  Originally, it was seen as a white substance that “bloomed” on flowering ash leaves and was called “manna”, after the biblical food.  It has a long history of use in modern medicine because it is able to cross the blood-brain-barrier, making it useful for treating injuries of the brain.  The Food and Drug Administration have given it their approval.

In laboratory test tube experiments it has also been found to prevent the protein alpha synuclein from forming aggregates, a significant finding which holds an important potential for treatment in PARKINSON’S DISEASE.  To test the ability of mannitol to break up alpha synuclein aggregates in the brain, the researchers, Ehud Gazit and Daniel Segal and their laboratory team designed a study comparing the abilities of both genetically modified and normal drosophila, or fruit flies.  The genetically modified flies to carried the human gene for alpha-synuclein and their performance was barely half of the performance of the normal flies.

So the researchers added mannitol to the diet of the modified flies for a period of 27 days and then repeated the experiment.  Amazingly, the modified flies were able to perform nearly as well as the normal flies.  On examination of the brains of the modified flies, the researchers found a 70 percent reduction in the aggregates of alpha synuclein in the brains of the flies fed a mannitol diet compared to those who had not had the mannitol diet.

Then Dr. Eliezer Masliah from the University of San Diego performed a similar study using mice genetically modified to carry the alpha synuclein gene.  He found that four months after the alpha-synuclein mice were injected with mannitol, they had a dramatic reduction in alpha-synuclein in their brains.

Future and present research involves looking at the structure of the mannitol molecule to find ways to attach other medications that could be carried across the blood-brain-barrier by this molecule.  More experiments with animal models, including behavior testing, will need to be carried out before any testing with humans can be attempted.  Finding the proper dosages and combinations that are effective and safe will take time.  Dr. Segal cautions people that taking mannitol in large quantities is not wise because the research on safety and effectiveness is still being tested and the effects of large doses of mannitol are not yet well understood.  He adds: “I don’t know whether mannitol will provide a cure; this may be too optimistic.  If we can slow down the disease, diagnose it early enough and reduce the amount of suffering, I will be more than happy.  I’m definitely hopeful.”

 

R. Shaltiel-Karyo, M. Frenkel-Pinter, E. Rockenstein, C. Patrick, M. Levy-Sakin, A. Schiller, N. Egoz-Matia, E. Masliah, D. Segal, E. Gazit. A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent  -Synuclein ( -syn) Aggregation Inhibitor: A NOVEL DUAL MECHANISM OF MANNITOL FOR THE TREATMENT OF PARKINSON DISEASE (PD)Journal of Biological Chemistry, 2013; 288 (24): 17579 DOI: 10.1074/jbc.M112.434787

S.Carnvek,  Sweet News for Parkinson’s Disease, Israel Ministry of Foreign Affairs, 04 May 2014

 

 

Review by Marcia McCall

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Wristband Aid To Help Manage Parkinson’s

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A MELBOURNE firm is expanding its production of wearable technology designed to help
Parkinson’s disease sufferers live a better quality of life.

The technology, a wristband called the Parkinson’s Kinetigraph, has a built-in accelerometer like the

common one found in smartphones and wearable tech devices such as the Jawbone Up and Fitbit Flex.

The Kinetigraph collects raw movement data which shows the symptoms of Parkinson’s disease.

Clinicians can use the data to finetune medication.

The Melbourne-based Global Kinetics Corporation managing director Andrew Maxwell said the firm

had developed two software algorithms that turned the wristband data into information discernible to

doctors.

Patients typically wore the device for 10 days. It measured the level of “bradykinesia” — the slowness of

movement patients experienced at the onset of symptoms. Bradykinesia typically is treated with

dopamine replacement therapy.

The device also measured “dyskinesia” — more advanced symptoms of Parkinson’s characterised by

involuntary muscle movements.

By finely tuning medication levels, sufferers could have more time in the near-to-normal state at the

beginning of symptoms, and hence an improvement in their quality of life through better movement, Mr

Maxwell said.

Having more precise data from the wristband would see patients receive the appropriate drugs at the right

time.

“We believe that the main focus that clinicians are interested to know about is what’s happening with the

patient’s bradykinesia and dyskinesia and the fluctuations between those two states,” Mr Maxwell said.

“You can most likely use oral therapies for longer without having to move to the more advanced

therapies for Parkinson’s which includes more invasive treatments, such as deep brain stimulation.

“You can also make a decision about how people are progressing with their symptoms and when is the

appropriate time for them to be moving to an advanced therapy,” Mr Maxwell said.

Global Kinetics, a private Australian company incorporated in 2007, has focused on Parkinson’s since its

inception, through the initial research and development phases to commercialisation and production.

The device was first developed at the Melbourne based Florey Institute of Neuroscience and Mental

Health through work undertaken by Professor Malcolm Horne and Dr Robert Griffiths. They co-founded

Global Kinetics Corporation.

The original Kinetigraph bands were launched in 2012, with 500 sold so far. They were sold to hospitals

which provided them to patients for 10 days’ medical surveillance.

The wristbands alert patients as to when to take prescribed medication and patients could time stamp

when they have taken it. Kinetigraphs are used in 50 hospitals in nine countries: Australia, Germany, the

Netherlands, Norway, Sweden, Denmark, Malaysia, Hong Kong and Thailand.

Global Kinetics was now seeking to penetrate the US and European markets and was hopeful of getting

US Food and Drug Administration approval this year, Mr Maxwell said.

He said Global Kinetics also was looking to expand the device’s functions. “We think the way things are

progressing more and more medical data collection will occur from wrist-worn sensors or sensors worn

on the body, and they will communicate with each other. More and more data will be connected and there

will be platforms that evolve to interpret the data over time.”

 

 

Article Credit:  Chris Griffith - THE AUSTRALIAN

Picture Credit: David Geraghty - News Limited

Wristband Aid To Help Manage Parkinson’s

“Lift” Spoon Not Just for Convenience

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“Lift” Spoon Not Just for Convenience

Lift Labs, a San Francisco based business, developed the “Lift” spoon basically to enable people with movement disorders and tremors to eat comfortably without spilling their “soup” before getting it from the bowl to their mouth.  The device senses a tremor when it is first picked up and uses stabilizers to counter the tremor, keeping the contents of the spoon steady.  It has a rechargeable battery so it will always be ready to use.  Lift Labs is promising more attachments beside the spoon, such as a fork and a key holder will be available soon.

Now a young researcher from the University of Michigan, Dr. Kelvin L. Chou, has found that the “spoon” is not just convenient, but actually helps reduce tremors.   This clever fellow tested 15 PARKINSON’S DISEASE patients on three different tasks: holding something in the spoon; eating with the spoon and transferring objects from the spoon to a cup about a foot away.  (He actually used small foam blocks instead of actual food.)  Subjects were tested with the “spoon” turned off and then again with it turned on.  While both subjects and the investigator were supposedly blinded, because of the effect of the device, true blinding might not be possible.

With the exception of two subjects hose tremors were so severe that use of the device was not helpful, the rest saw a reduction of their tremors of between 71% and 76% as measured with an accelerometer.  Using the Fahn-Tolosa-Marin Tremor Rating Scale (TRS), all subjects showed a significant improvement on all three tasks when the device was turned on.  Improvement in this case meant going from “spilling to minimal spilling”.  Tremor was still present, but most of the subjects were impressed with the device and wanted to buy one when it becomes commercially available.

The device, called the Lift Ware Stabilizer, is now available and can be ordered from liftlabsdesign.com.  It costs $295.00, but comes with a 30-day money back guarantee.  Lift Labs says the cost works out to about 27 cents a meal for a year.

Handheld Device Reduced Tremors. Medscape. Mar. 11, 2014

 

Review by Marcia McCall

 

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Early Assessment of Dementia Risk in PARKINSON’S DISEASE

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Early Assessment of Dementia Risk in PARKINSON’S DISEASE

 

PARKINSON’S DISEASE is usually considered a “movement disorder”, with symptoms of tremor, rigidity and slowness that affect a person’s ability to move.  But a small percentage of people diagnosed with PARKINSON’S DISEASE go on to develop cognitive impairments, dementia or even Lewy body dementias.

“This study opens the door to further research, for example, on medication or on non-pharmacological approaches such as transcranial magnetic stimulation.  It’s important for these patients to be identified very quickly before they develop dementia so that a therapeutic approach can be adapted to their specific needs”, says Dr. Oury Monchi, the principal investigator of this study.

Dr. Monchi and Dr. Hanganu and their team of researchers affiliated with the Universitè de Montrèal, used magnetic resonance imaging to find there was a thinning and atrophy in some brain regions of people with mild cognitive impairment who were diagnosed in early stages of PARKINSON’S DISEASE.  They discovered that as the disease progressed, the thinning and atrophy of these areas progressed along with an increase in cognitive decline.  The study followed a cohort of 32 subjects in the early stages of PARKINSON’S DISEASE and a control group of 18 healthy subjects for a period of 20 months.

Cortical thinning has been proven to occur corresponding to the progression of the disease but has not been studied in relation to the development of cognitive impairment.  This study found a more rapid progression of thinning in the temporal, occipital, parietal and supplementary motor areas of patients with mild cognitive decline as compared to patients who had no cognitive impairments and healthy controls. They also found that the amygdala and nucleus accumbens also lost significant volume in patients with cognitive impairments. As a specific pattern of deterioration in these brain regions correlates to the presence of mild cognitive impairment in the early stages of PARKINSON’S DISEASE, these findings could lead to a biomarker predicting the subsequent development of dementia.

A. Hanganu, C. Bedetti, C. Degroot, B. Mejia-Constain, A.-L. Lafontaine, V. Soland, S. Chouinard, M.-A. Bruneau, S. Mellah, S. Belleville, O. Monchi. Mild cognitive impairment is linked with faster rate of cortical thinning in patients with Parkinson’s disease longitudinallyBrain, 2014; DOI:10.1093/brain/awu036

 

Review by Marcia McCall

 

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Predicting Cognitive Decline in PD from Alpha Synuclein in Cerebral Spinal Fluid

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Predicting Cognitive Decline in PD from Alpha Synuclein in Cerebral Spinal Fluid

A new study being published in the April issue of the American Journal of Pathology has looked at data from 304 subjects from a study begun in 1987 that was one of the earliest studies that collected and catalogued specimens from early onset and newly diagnosed people with PARKINSON’S DISEASE and followed them for up to 8 years.  That study was the Deprenyl and Tocopherol Antioxidative Therapy of Parkinson’s (DATATOP) that found it possible to control symptoms and delay initiating treatment with levodopa by using Deprenyl.  It was a wide reaching study that led to a better understanding of the progression of the disease and the search to develop more neuroprotective therapies for PARKINSON’S DISEASE.

This new study was unique in that it drew on the data collected over a long period of time previously and did a new analysis of that information to find a connection to cognitive change or dementia related to levels of alpha synuclein found in samples of cerebral spinal fluid (CSF).  Levels of alpha synuclein in CSF were found to generally decrease as the disease progressed, but in some cases it was noted that higher levels of alpha synuclein were found in the CSF of subjects whose scores showed greater cognitive decline in the cognitive tests.  Subjects with more rapid cognitive also had relatively higher levels of alpha synuclein in their CSF.

The original study was divided into phases; Phase one was from entry into the study and Phase two started when the treatment with levodopa began.  All subjects enrolled in that study were in very early, untreated stages of PARKINSON’S DISEASE and without any symptoms of dementia. Cognitive testing was performed at entry and repeated every six months.  The United Parkinson’s Disease Rating Scale (UPDRS) cognitive testing section evaluated multiple aspects of cognition, including verbal learning, memory, visuospatial working memory and processing speed.  During Phase two cognitive changes became evident and were apparent across all sections of the cognitive testing. This data was carefully analyzed to control for age, sex, education, exposure to study drug and the actual dose of levodopa.

This research was done at the University of Washington (Seattle) School of Medicine, Department of Pathology under the direction of Jing Zhang, M.D., Ph.D.  First author is Tessandra Stewart, Ph.D.

“Cerebrospinal fluid alpha-synuclein predicts cognitive decline in Parkinson disease progression in the DATATOP cohort,” by Tessandra Stewart, Changqin Liu, Carmen Ginghina, Kevin C. Cain, Peggy Auinger, Brenna Cholerton, Min Shi, Jing Zhang, and the Parkinson Study Group DATATOP investigators (DOI:dx.doi.org/10.1016/j.ajpath.2013.12.007), The American Journal of Pathology, Volume 184, Issue 4 (April 2014)

 

Review by Marcia McCall

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http://www.telegraph.co.uk/health/healthnews/10029205/GPS-tags-for-dementia-patients.html

An Electronic Patch to Simplify Treatment

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An Electronic Patch to Simplify Treatment

Imagine that you get up one morning and don’t have to take a pill or count the hours until the next dose!  Imagine that the medication is delivered precisely and directly to your body according to your body’s actual state of need.  Such a delivery technique could smooth out all the peaks and valleys and keep PARKINSON’S DISEASE under control and your life running smoothly.  This dream is close, very close, to becoming a reality.

An international collaboration of scientists is working hard to make this dream a reality. The first step was idea of John Rogers, a materials scientist at the University of Illinois. He developed a membrane so thin that it could be combined with nano scale electronic semiconductors. Thus, the idea of “epidermal electronics” as a patch that could monitor various vital signs through the skin.

A Korean study in a lab at Seoul National University, headed by Dae-Hyeong Kim who is assistant professor in chemical and biological engineering also developed a thin patch that could monitor subtle tremors and release medication stored in nanoparticles and at the same time record all the data for retrieval later.  The work of the Korean Lab collaborated with a new company, called MC10, in Cambridge, MA that has been set up specifically to advance the concept of “stretchable electronics” that will further the development of the epidermal electronic patch. Rogers is a co-founder of this company along with Roozbeh Ghaffari.

In a paper recently published in Nature Nanotechnology, the researchers describe a device that is thin as a temporary tattoo making it virtually unnoticeable and as flexible as a stretchy band-aid.  This device will be composed of multiple layers of ultra thin membranes embedded with nanoscale sensors that can distinguish and measure the tremors of PARKINSON’S DISEASE from ordinary movements. It will also measure other vital signs, such as blood oxygen, temperature, and heart rate and store that data in a memory.  Ultimately, the data will be able to be down loaded to a smart phone or streamed directly to other communication devices, but that technology is still under development.  The patch could also contain unique medication delivery system where the medication is directly released into the skin as needed based on the data from the other systems.

This device is still in prototype form, and testing in humans is still a few years off.  It will take time to perfect the technology and obtain the necessary regulatory approvals.  While this group is currently targeting movement disorders such as PARKINSON’S DISEASE, other applications for this product could successfully treat diabetes or migraine headaches.  Drug delivery via a patch on the skin is not new.  What makes this research exciting is the addition of elements to monitor vitals and store or transmit that data while at the same time providing a controlled release of medication.  Mr. Ghaffari points out that this device can “take the epidermal electronics and couple it with memory on board and therapy. You can close the loop from diagnosis to therapy on a single patch.”

 

Multifunctional wearable devices for diagnosis and therapy of movement disorders: Dae-Hyeong Kim, et al; Natur Nanotechnology (2014) doi:10.1038/nnano.2014.3
A Bandage That Senses Tremors, Delivers Drugs, and Keeps a Record; David Talbot; MIT Technology Review; April 1, 2014

 

Review by Marcia McCall

 

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Genetics of Parkinson’s Disease is Topic of New Research

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Genetics of Parkinson’s Disease is Topic of New Research

The Parkinson’s Progression Markers Initiative  (PPMI) is an ongoing study looking for biomarkers in biological samples and imaging data from an international base of people with Parkinson’s disease who are part of a large national study.  Presently, over 800 individuals are involved with PPMI clinical trials at 32 sites.  In looking for biomarkers, such as a particular blood substances, or other physical processes that might predict the risk of PARKINSON’S DISEASE, researchers are hoping to find ways and means to both predict and treat the disease as early as possible and to target areas where drugs can be developed faster and more effectively.  Symptoms that have a demonstrated risk factor are loss of sense of smell and sleep behavior disorders are the subjects of other areas of research the PPMI. This study has already identified some blood markers such as the LRRK2 gene and the presence of alpha synuclein (SNCA gene) that are clearly connected to the disease, but the mechanism of operation is not yet clear.

Now they are further refining the search and are enrolling 250 subjects who are known to carry these genes and have symptoms of PARKINSON’S DISEASE and another 250 subjects who carry the genes but have no symptoms.  These subjects will be followed for at least 5 years.  At present, only about five or ten percent of all people with PARKINSON’S carry the genetic mutation.  However, knowledge learned from the genetics of these people will ultimately inform better understanding of the disease process. Of special interest are people of Eastern European descent who have relatives affected by PARKINSON’S DISEASE.

“Studying individuals with genetic mutations associated with PARKINSON’S can accelerate our research toward a PD biomarker and more effective treatments: said Stuart Factor, D.O., who is director of the Emory University Comprehensive Parkinson’s Disease Center and the director of the Emory Movement Disorders Center.  The large-scale extent of the PPMI research is already bringing scientific insights that will strengthen the efforts to find therapies that will modify or change the course of this disease.  This is an observational study that is seeking information and samples from participants.  Participants will not be involved in taking any experimental medication or undergoing any experimental procedures. Individuals who would like to be a part of this large undertaking should visit the Michael J. Fox Parkinson’s Progression Markers Initiative web page for further information.

 

http://medical express.com/news/2014-03-genetics-parkinson-disease.html

 

written by Marcia McCall

 

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Endocannibinoids to Rescue Parkinson’s Brains

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Endocannibinoids to Rescue Parkinson’s Brains

A recent study from the lab of Robert Malenka, MD, PhD, Pritzker Professor of Psychiatry and Behavioral Sciences at Stanford University Medical School, has found naturally occurring endocannabinoids (substances similar to the active compounds in marijuana) in the brain that when stimulated, contributed to a dramatic improvement in mice with a condition like Parkinson’s.

Endocannabinoids, naturally synthesized marijuana like substances that occur in the brain were discovered in the late 1980s and research in the early 1990s found them to be essential bio-regulation.   Research suggests they have a role in inflammation and endocrine activities and also serve as messengers for other neurological and immunological conditions.  Cannabinoid receptors are located all over the brain, however their roles and functions are still being researched.  It is not known why they are not always activated by naturally occurring endocannabinoids

Dr. Malenka and his post-doctoral researcher, Anatol Kreitzer, PhD, focused their attention on the striatum, because it is prominent to multiple neurological disorders, including PARKINSON’S DISEASE.  Dopamine is the principle neurotransmitter in the striatum, which when depleted, causes the loss of movement and rigidity experienced by people with PARKINSON’S DISEASE.  While studying the striatum, they became aware that there were many cell types that appeared alike under the microscope, but only became distinguishable when mice were specially bred to have specific cells stained with fluorescent dyes.  With two cell types clearly identified, they were able to probe communication and activity between the cells.  They identified a unique interaction between those two cells.  One cell was involved with initiating movement and the other with restraining movement, and acting together to determine appropriate movement.  Endocannabinoids are the “messengers” that use dopamine to cause the cells to interact.  When dopamine is absent, the endocannabinoids begin to break down, causing the initiation of movement to halt and restraint of movement to become dominant.

Introducing more dopamine into the brains to the mice resulted in only a slight improvement in movement. Using a new drug to halt the enzymatic breakdown of the endocannabinoids did nothing.  But introducing a combination of dopamine replacement and the enzyme that stopped the breakdown of the endocannabinoids resulted in the mice going from completely frozen to being able to move freely in only 15 seconds.

This study is exciting on many levels, from distinguishing the subtle differences in cell types in the striatum, to finding the communication loops between previously inconspicuous cells and mostly from finding a way to restore the balance to that interrupted cell circuitry to initiate the return of movement in the Parkinson-like mice.  While it is immediate good news for the mice involved, it will still be quite a matter of more research and time before the implications of this study are fully researched and the results translated to good news for human studies.  It does reveal a potential new therapeutic approach to finding better treatment for the symptoms of PARKINSON’S DISEASE.

Source:

Stanford School of Medicine News Release 2-27-14

 

Review by Marcia McCall

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Medical Marijuana and Parkinson’s Disease

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Medical Marijuana and Parkinson’s Disease

When you are in pain, and stiff and suffering from PARKINSON’S DISEASE, you want something, anything, that will bring relief.  And members of a certain generation probably tried marijuana, long before they had PARKINSON’S DISEASE and found the results pleasurable.  Now, when those same pleasurable effects could soothe the strain of a disabling disease, political controversy impedes the Food and Drug Administration from being able to conduct the necessary research and clinical trials.

An observational study recently done in Israel showed considerable improvement in tremors, muscle rigidity, pain when subjects were tested 30 minutes after inhaling marijuana. Twenty subjects, all about 66 years of age and diagnosed with Parkinson’s Disease for over 7 years, were tested using the Unified Parkinson’s Disease Rating Scale (UPDRS) both before and 30 minutes after smoking cannabis in the clinic.  Their scores on tremor, rigidity and bradykinesia all decreased significantly and the subjects claimed the benefit lasted for 2 or 3 hours after smoking.  Fine motor skills were also improved and 12 of subjects reported major improvements in their sleep while 8 said that their sleep was somewhat improved.  While this study had some limitations, that there were no control subjects and it was of a limited size and a short duration, it does demonstrate a therapeutic benefit for both motor and non-motor symptoms, which should lead to more in-depth studies.  The potential of marijuana treatment for subjects who have limited or no response to standard medications must also be closely considered.

Another small study done in the Czech Republic queried 339 subjects with PARKINSON’S DISEASE on whether or not they had used marijuana.  One quarter of them responded that they had and 45 percent of them noted that their symptoms had been helped.

The above are recent examples of research on cannabinoids, but any serious researcher can find some of the earliest mentions of the use of marijuana in medicine go back thousands of years. The Chinese Emperor, Chen Nung, who is considered the father of Chinese medicine, discovered the medicinal properties of not only marijuana, but ephedra and ginseng.  He lived around 2700 B.C.   In 1700 B.C., the Egyptians in written medical records, referred to therapeutic marijuana use.  In 1500 B.C. the Chinese pharmacopoeia, Rh-Ya, has a written entry for marijuana as a medicine.

There are many records of cannabis sativa used for medical purposes from earliest recorded history to present time–even records kept by the U.S. presidents George Washington and Thomas Jefferson about the hemp (marijuana) that they were growing in their own plantations.  Early records indicate it was useful for relieving nausea, improving appetite, improving depression, and as pain reliever. Later it was found to relieve the pressure of glaucoma in the eye.  Marijuana as medicine has a long history.

It was not until the late 1800s when the western world saw a development of a moralistic era of prohibitions that medical marijuana came into a decline.  The prohibitionists were against not only marijuana, but alcohol, gambling, prostitution and other commonly used narcotics, such as opium and laudanum.  In 1915, President Woodrow Wilson signed the “Harrison Act”, which became the model for all future drug regulation legislation and lead to the “Marijuana Act” of 1937, which effectively criminalized any use of marijuana.

Interestingly, almost 100 years later, public acceptance of marijuana for medical purposes is high and the legislative action is changing.  Here in Florida, the legislators are drawing up new regulations not so much with “If’ medical marijuana is approved as for “When”.  The referendum that will be on the November ballot: “Allows the medical use of marijuana for individuals with debilitating diseases as determined by a licensed Florida physician.  Allows caregivers to assist patients’ medical use of marijuana….”

 

Review and article written by Marcia McCall

 

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Straightening the Mis-Folded Proteins of Alpha-Synuclein

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Straightening the Mis-Folded Proteins of Alpha-Synuclein

Alpha-synuclein if the protein molecule that is found in Lewy bodies and is one culprit that is thought to be responsible for the symptoms of PARKINSON’S DISEASE.  Scientists have been working hard to understand how alpha-synuclein infiltrates the cells and neurons and exactly what its role is in human biology.  It is known that alpha synuclein is at the root of many of the problems of neurodegenerative diseases, but how to remove or suppress this protein has proven extremely elusive and resistant to the best of scientific techniques.

Dr. James Shorter, an associate professor of Biochemistry and Biophysics from the Perelman School of Medicine at the University of Pennsylvania may have discovered a unique and interesting approach that could help solve the alpha synuclein dilemma.  His research looked at yeast proteins, and he discovered a specific yeast protein Hsp104 that is able to dissolve mis-folded proteins of alpha-synuclein in the plasma of cells.

Unfortunately, it is not so simple and straightforward.  Hsp104 is one of the better known proteins on our planet; however, it does not exist in humans or animals.  Dr. Shorter says “We don’t understand why animals have lost the gene for Hsp104, but at the same time, we’ve been wondering:  ‘Is there a therapeutic opportunity in this?’”  His research has shown that although Hsp104 is effective, it is not perfectly effective and increasing the effectiveness of this protein is the new direction in his research.

His lab has been re-engineering variants of Hsp104.  Finding the right variant that can suppress the mis-folded alpha synuclein while also improving the function of the cell is the challenge.  While any number of variants might to the job, they might also do more than prevent the clumping of alpha-synuclein and therein would lie some serious problems.  So it is no easy task to engineer this particular protein to become an accurate therapeutic product with a focused target.  It is also a protein that is foreign to animal and humans, so side effects or toxicity are also important considerations.

His research up until now has been with yeast models, and has been successful.  The next step was to test it in a more sophisticated, multi-cellular model, for which a primitive worm model was chosen.  This work was a collaboration with Dr. Guy Caldwell from the University of Alabama.  And it was successful.  The next challenge is to move to even more complex animal models, such as mice.

Although this research is still in some very early stages, it is exciting that a foreign molecule can be engineered to obtain therapeutic benefit and holds the promise that perhaps eventually it will become an important agent for ameliorating the symptoms or possibly eliminating the cause of those symptoms in PARKINSON’S DISEASE and other neurodegenerative diseases.

Jackrel, M.E., M.E. DeSantis, B.A. Martinez, L.M. Castellano, R.M. Stewart, K.A. Caldwell, G.A. Caldwell, and J. Shorter^. (2014). Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell. 156:170–182

 

Review by Marcia McCall

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