Parkin is a protein that is associated with the PARK2 gene. Mutations of the Parkin protein are associated with young on-set and familial forms of Parkinson’s. The role of Parkin in cells is to regulate the function of the mitochondria, or the little energy furnace of the cell. Mutations in the Parkin gene lead to instability of the Parkin protein which can be very debilitating in nerve cells, a mechanism that is not yet fully understood.
One of the roles of Parkin is to remove damaged proteins in the mitochondrial outer membrane and eliminate them. Research suggests that problems in this pathway may be the cause of Parkinson’s. Parkin also has other roles in cell signaling as well as in suppressing tumors. With so many biological roles, understanding how Parkin interacts in so many domains is essential.
In order to investigate some of these interactions, two young researchers at the MRC Laboratory of Molecular Biology in Cambridge, England, have crystallized a form of human Parkin into a three dimensional structure. Using X-ray diffraction patterns to create the three dimensional structure they were able to see how the protein actually folds. The Parkin protein structure is controlled by an internal regulation system, which is lost when it is affected by mutations that account for Parkinson’s disease.
When Parkin is functioning properly, it is may be able to protect the cells and lead to their longevity, and by its other roles, some of which are yet unknown, protect against the risk of Parkinson’s and other diseases. The three dimensional crystal structure of this protein created by these young researchers is already unlocking some of the secrets of Parkin.
Tobias Wauer, Daid Kommander. Structure of the human Parkin ligase domain in an autoinhibited state. The EMBO Journal, 2013: DOI: 10.1038/emboj.2013.125
Does your bed mate complain that you fight in your sleep? Do you dream of being chased by wild animals about to devour you? Do you physically try to fend them off? Sleep disturbances, especially when they feature trying to escape from wild animals, are a sign of impending neurodegeneration. People with Parkinson’s often have dreams with physical aggression such as fighting with animals. And people who act out the actions of their dreams have a very high risk of developing Parkinson’s within 10 to 15 years. But the question now is which is the cause and which is the effect. Does early stage neurodegeneration lead to sleep disturbance or is it the sleep disturbance that leads to neurodegeneration?
Rapid Eye Movement (REM) sleep and non REM (NREM) sleep are normal patterns of human sleep. During REM sleep, rapid eye movements are accompanied by a paralysis of the muscles, except for the diaphragm to allow for breathing. In REM sleep behavior disorder (RBD) the sleeper’s muscles are active and he acts out the disturbances of his sleep, sometimes with vocalizations. Periods of RBD can range from mild movements to violent thrashing about, sometimes injuring the sleeper or harming his bed partner. This behavior can also change over time; it can be mild when young progressing to more violent over the years. While it is sometimes observed in younger patients, it affects mostly men over 50. Presently, there are medications to help alleviate some of the problems and permit the sleeper to get a good night’s rest.
Parkinson’s disease has a long period of slow development; it can take years for the symptoms to progress to the point of concern. Symptoms such as depression, anxiety, anemia, constipation and loss of smell can seem to appear independently along with aging without anyone suspecting that they are strong predictors of neurodegeneration or Parkinson’s. Studies of RBD have shown that the sleep disturbance is accompanied by synuclein inclusions in the brain, which are definite precursors to neurodegenerative diseases.
This scenario gives researchers plenty of areas to study–the relationship between RBD and the development of Parkinson’s holds much promise. The first is the potential to test disease predictors i.e. does RBD predict Parkinson’s? Secondly it presents the opportunity to study the long period of development of Parkinson’s with imaging techniques such as trans cranial ultrasound, Single Photon emission computed tomography (SPECT) and dopaminergic imaging. And finally, the potential to develop neuroprotective therapies.
Given the already strong relationship between RBD and neurodegenerative disease, it is important for neurologists and other professionals to identify this as a pre-motor symptom and to use this information to provide serious counseling to the patients who are at risk.
*Postuma, R.B.;Gagnon, J-F.; Montplasir, J.Y. REM Sleep Behavior Disorder and Prodomal Neurodegeneration – Where Are We Headed?; Tremor Other Hyperkinet Mov (NY) 2013; 3 tre-03-134-2929-1
A group of researchers from the Research Center Hospital San Mateo in Pavia, Italy examined over 100 recent studies of toxic materials used as pesticides and solvents and found a high correlation with the risk of developing Parkinson’s disease by people who used them. These are often the people who work on farms or in landscape or horticultural industries..
Pesticides are types of toxic chemicals or biological agents usually identified by the type of pest they are designed to control. Herbicides are used to control unwanted plant materials in food crops, ornamental plants and lawns and meadows. Controls for specific types of insect or rodent pests are also included in pesticides. Some pesticides are applied as liquid, others as powders and still others are used a bait.
Specific chemicals or combinations of chemicals were not differentiated in this survey study, nor were the methods of application or strength of the agent reviewed. The main criteria examined was the length of time workers had been using the products. It was noted that the risk of developing Parkinson’s increased in a dose response manner as the length of exposure to the chemicals increased. People utilizing these chemicals had between 30 and 80 per cent increased risk.
Also included in the review materials was exposure to the chemical solvent used in the dry cleaning industry, trichloroethylene . Previous studies of this solvent have noted a 5 times greater risk of developing Parkinson’s.
The analysis of over 100 studies does show a causative role for pesticides and solvents in neurodegenerative disorders in people who work with them. However more studies are needed to understand how people who may be exposed to these chemicals in hobby gardening or in residential maintenance or people who wear clothing that has been dry cleaned may be affected by these agents. Of even more importance, is the diet of people who consume the fruits, vegetables and grains that are grown in fields treated with these chemicals.
The Supreme Court of the United States is presently considering a very interesting case with serious consequences for Parkinson’s research. They are expected to issue their ruling by the end of June.
This case involves a company based in Utah that has obtained patents on two specific genes and developed specialized tests based on these genes. Presently, Myriad is the only company who is able to test for these genes and the cost of this testing, about $4,000 must be borne by the patient or, more likely, their insurance company. The two genes involved are BRCA1 and BRCA2 which are linked to hereditary breast cancer. However, the tests originally developed actually missed about.10% of the cancer in the mutated genes. So they developed another test, and added $650 to $700 more to the testing process.
There are several other diagnostic genetic testing companies that also hold patents on testing for specific genes – and the profits from these tests are not small. One study by the United Health Group found that over $5 billion a year is spent on genetic testing for about 2,500 conditions in the U.S. One such company is 23andMe, which has the only testing protocol for familial Parkinson’s gene in this country. Anyone who wants to know if they carry this gene must use the kit from 23andMe.
The question the Supreme Court is asking is “are genes patentable?” And, like most cases, there are two sides to this debate. Research is expensive and companies who develop specific tests on specific genes depend of the income generated during the 20 years of the patent’s life to recoup their initial expense and pursue more avenues of research. But if the gene itself is patented, that places the gene out of the reach of other researchers by making it too expensive to obtain and forcing them to go through a complicated process of obtaining permissions. This stand in the way of further research or developing other ways of using it. It interferes with doctors’ ability to conduct clinical research and treat patients. These researcher feel that a gene is a part of nature and nature is not patentable. Patents are issued for inventions, but genes are part of our DNA.
The company holding the patents claims that once a gene is extracted from the chain of DNA, it has been manipulated and therefore is no longer a simple part of nature, that the manipulation separates it from nature and makes it comparable to an invention.
This is a philosophical as well a practical dilemma, with wide ranging implications for the future of medical research and development of tests and treatments. Patents may encourage investors to back certain types of research and protect their investments. On the other side is the question of human dignity: is not human DNA intrinsic to one’s body and therefore part of one’s very nature? Are patents even the right way to even think about developing and financing research along these lines?
The United States Supreme Court is not alone in considering these issues. Australia is also considering the same charges against this company. It may take the Supreme Court longer than June 30th to clarify the issues and render its decision. Whatever the decision, the companies working with genetic testing are probably going to have some changes in their future.
Peripheral neuropathic pain in Parkinson’s disease has been reported to be seven times higher than in a normal population. It has variously been attributed to insufficient vitamin B-12, perhaps from long term used of levodopa replacement medications or even to levodopa itself causing demyelination of neurons that transmit pain impulses. In another disease, Charcot-Marie-Tooth (CMT) disease it results from a genetic mutation. The principle of the cause of this demyelination process in CMT has been identified and it is hoped that it will lead to treatments to alleviate this pain not only in CMT but Parkinson’s and other diseases as well.
Lawrence Wrabetz, M.D. and colleagues at the Hunter James Kelly Research Institute in Buffalo, New York, along with other European researchers have identified the mechanism by which proteins in the myelin sheath are mis-produced and found the gene that also interferes in this mis-production process. The sheath is composed of Schwann cells which produce myelin in nerve cells. When the proteins that produce those cells begin synthesizing mutated proteins, a gene called Gadd34 turns on and causes them to reproduce those mutated proteins at a much higher level, thereby increasing the problems in the myelination process.
Dr. Wrabetz’s team has also identified a way to improve myelin production with the addition of a small molecule drug. When salubrinal, a small molecule drug is added in both laboratory cultures and animal models of CMT Gadd34 is effectively reduced. It partially turns off the protein syntheses process and helps restore myelination.
While Dr. Wrabetz disease model has been Charcot-Marie-Tooth disease, his main research has involved understanding myelination disorders in general. He thinks that there may be one unifying underlying mechanism and that what applies to one disease may also apply to others. If they are successful in finding a safe and effective dose for humans of salubrinal, the suffering from painful neuropathies will hopefully become a thing of the past.
This study looks at the association between depression and Parkinson’s disease (PD) in a study group of 992 PD patients that were diagnosed after 2000. The diagnosis of depression and Parkinson’s Disease were self-reported. The conclusion drawn from this study is that a depression diagnosis before 2000 was in fact associated with higher levels of PD. However, it is important to note that this study does not explore other moderators such as poor health status. The authors conclude that depression may either share etiological factors with Parkinson’s Disease or that depression may in fact be an early symptom of PD. Further study into this topic is needed.
Full article: – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914462/
Alpha-synuclein (α-synuclein) is one of the three members of the synuclein family, small proteins that are present in human brains and whose normal function there is not yet completely known or understood… What is known is that accumulations of α-synuclein accumulate in the neurons of Parkinsonian brains over the course of the disease.. The pathological mechanism behind exactly how α-synuclein forms the aggregates found in Lewy bodies (named for the German neurologist, Friedrich Lewy, who first described them) has not been understood. Animal models of this disease have not been found or as yet developed to help researchers study this disease.
But now a group of researchers from the German Center for Neurodegenerative Diseases in Bonn, Germany under the direction of Professor Donato DiMonte have developed an experimental model in rats that may help to explain how α-synuclein, or abnormal forms of α-synuclein, spread throughout the brain, and lead to finding ways to slow or even stop its progression and the progression of Parkinson’s disease.
In human pathology it has been noted that α-synuclein production usually starts in the lower regions of the brain, in the medulla oblongata, and with the progression of the disease moves to higher regions where it accumulates gradually. It appears to follow a typical pattern which was thought to pass through a pathway of interconnected neurons, but until now, there was no way to visualize this process.
Dr. DiMonte thinks that since there is good reason to believe that Parkinson’s actually starts in the medulla oblongata and because it is a very difficult region to reach surgically, this rat model would help solve some of the issues.
Dr. DiMonte’s group developed a viral particle carrying a human DNA form of α-synuclein and injected it into the vagus nerve in the rats’ neck. The genetic code for the human α-synuclein passed into the rats’ neurological system and into the medulla oblongata where it began producing high quantities of human α-synuclein. After two months, they found the α-synuclein that originated in the medulla oblongata migrated to other higher areas of the rats’ brains. Over more time, the concentrations of α-synuclein actually increased, mimicking the pathology seen in Parkison’s. They were able to map the specific nerve tracts and note the morphological changes in the nerve projections that absorbed the human α-synuclein.
This is an exciting first study that will lead to better understanding of the progression of not only Parkinson’s disease, but other diseases such as Alzheimers that have an accumulation of α-synuclein. Future studies could lead to therapeutic treatments that target either the production of α-synuclein or its accumulation and transmission to regions in the brain.
This article is a review of literature and studies involving perception in individuals with Parkinson’s. A review of empirical evidence suggests that individuals living with Parkinson’s Disease have possible deficits in the perception of speech concerning loudness, as well as perception of verbal emotions. The casual and nature of perceptual deficit are largely undetermined and need to be further researched.
See the Full article here – Parkinsons Disease Overview
The diabetes drug is Byetta and its generic name is exenatide. This drug was developed for Type 2 Diabetes but may be able to improve cognitive and motor function in Parkinson’s disease. A small study of 44 patients conducted by Dr. Thomas Foltynie from the National Hospital for Neurology and Neurosurgery in London has shown promise.
Of the 44 Parkinson’s subjects, 20 received twice daily injections of exenatide. Byetta (exenatide) is designed as a pen type device for self injection. Given the expense of manufacturing placebos into such a device, the control group received nothing. Subjects were followed for a year and evaluated periodically by a blinded investigator. Multiple rating scales were employed and subjects were rated both on and off medication at regular intervals throughout the study. At the conclusion of the study, investigators found that the subjects who received exenatide showed an almost 3 point improvement in both motor and cognitive function while the control group had a 2 point decline. Weight loss was the only side effect. .
But while the benefit and improvement seen in the control group is sufficient reason to initiate more statistically relevant clinical trials, there is another perhaps even larger benefit. This clinical trial utilized a medication that is already FDA approved and its basic safety and tolerability were already known. Given the enormous expense, the long period of development and animal studies and the risks involved in developing and studying new treatments or drugs for neuroprotection, this study was much more cost efficient as well as being a very rapid way of collecting information about the effectiveness and tolerability of this drug in a new population. Clearly, the results of this one small study are not sufficient to determine the efficacy of exenatide for Parkinson’s however, it does speed up the process of making more options available for symptomatic relief of Parkinson’s.
Can a simple test to detect the loss of the sense of smell be useful in making earlier and more accurate diagnoses of Parkinson’s? A team of Dutch researchers think so. At least 90% of all Parkinson’s patients experience loss of their sense of smell, and many studies have verified this. This study found an easy and inexpensive test that can be used in a clinical setting to help diagnose PD accurately .
This clinical trial recruited much larger numbers of participants than many trials which are sometimes limited by having fewer Parkinson’s patients. This gives this trial’s accuracy a stronger and more favorable outcome. 296 people were enrolled, 148 as age matched healthy controls and 148 Parkinson’s patients. The PD patients were divided into three groups by symptoms: rigidity as dominant symptom, . tremor as dominant or other symptoms.
All participants were asked to identify 16 different odors to identify which odors would be appropriate for a more sensitive test. “Sniffin’ Sticks”, a product specific for olfactory testing, were used enclosed in felt tip pen cases to conceal their identities. Odors included food odors such as fish, peppermint, coffee, cloves, cinnamon, etc and non food odors such as rose, gardenia, leather, etc. Food odors had the best sensitivity ratings and were then narrowed down to eight and then again down to three. Ultimately, the three odors that demonstrated the best sensitivity contrast between healthy controls and Parkinson’s were coffee, peppermint and anise.
All the healthy controls were able to identify these odors and only 10 of 148 in the Parkinson’s group. This appeared to be age related responses from younger members of the Parkinson’s group; however younger members (ages 45 – 65) of the PD group already showed significant olfactory impairment compared to the age matched controls. Severity of the disease also was important. The group that was rigidity-dominant had slightly more olfactory impairment than the tremor group. Cognition was another indicator of odor impairment, but the results were sensitive to the type of cognitive testing used. Women and smokers showed a somewhat lower risk for impairment.
Results of this trial show a strong correlation between sense of smell and Parkinson’s. Testing odor identification can be a useful supportive diagnostic tool for Parkinson’s. A brief three odor smell test in a clinical setting is a non-invasive, cost effective tool that could help both patients and neurologists.