Parkinson's disease: Study focuses on regulation of dopamine levels

Date:

December 11, 2014

Source:

Institut de recherches cliniques de Montreal

Summary:

A mechanism regulating dopamine levels in the brain has been revealed by a study on a mouse model of late onset Parkinson's disease. Using gene expression profiling, a method to measure the activity of thousands of genes, researchers investigated dopaminergic neurons in the midbrain, which are nerve cells that use dopamine to send signals to other nerve cells. These neurons are known to degenerate in Parkinson's disease.

Researchers in Montréal led by Jacques Drouin, D.Sc., uncovered a mechanism regulating dopamine levels in the brain by working on a mouse model of late onset Parkinson's disease. The study, conducted in collaboration with Dr. Rory A. Fisher from the Department of Pharmacology at the University of Iowa Carver College of Medicine, is published online by the scientific journal PLoS Genetics.

 Using gene expression profiling, a method to measure the activity of thousands of genes, researchers investigated dopaminergic neurons in the midbrain, which are nerve cells that use dopamine to send signals to other nerve cells. These neurons are known to degenerate in Parkinson's disease.

"We identified the Rgs6 gene for its restricted expression in dopaminergic neurons," explains Dr. Drouin, Director of the Molecular Genetics laboratory at the IRCM. "We had previously shown that this gene is itself controlled by a transcription factor called Pitx3, which plays an important role in the survival of these neurons

Through our study, we discovered that a defective Rgs6 gene causes the death of these neurons," adds Dr. Drouin. "More specifically, we found that when we remove the Rgs6 gene, this relieves a brake against excessive dopaminergic signalling. As a result, excess free dopamine accumulation causes cellular stress, which, in turn, causes the neurons to die. Our work thus indicates that Rgs6 could be a new target for the development of drugs against Parkinson's disease."

According to Parkinson Society Canada, nearly 100,000 Canadians have Parkinson's disease. This progressive neurodegenerative disease primarily affects voluntary, controlled movement. It results from the loss of cells responsible for producing dopamine, which acts as a messenger between brain cells that control the body's movements.

Story Source:

The above story is based on materials provided by Institut de recherches cliniques de Montreal. Note: Materials may be edited for content and length.

Journal Reference:

1 Panojot Bifsha, Jianqi Yang, Rory A. Fisher, Jacques Drouin. Rgs6 is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra. PLoS Genetics, 2014; 10 (12): e1004863 DOI: 10.1371/journal.pgen.1004863

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Stem Cells from Adult Nose Tissue Used to Cure Parkinson's Disease in Rats

NEWS ARCHIVESRead News

Friday December 05, 2014

PRWEB

Digital Journal - Scientists have for the first time used adult human stem cells to "cure" rats with Parkinson's disease, a neurodegenerative illness that currently has no cure. The study, published in the current issue of STEM CELLS Translational Medicine, details how a team of researchers working in Germany at the University of Bielefeld (UB) and Dresden University of Technology were able to produce mature neurons using inferior turbinate stem cells (ITSCs).

ITSCs are stem cells taken from tissue that would generally be discarded after an adult patient undergoes sinus surgery.

The team then tested how the ITSCs would behave when transplanted into a group of rats with Parkinson's disease. Prior to transplantation, the animals showed severe motor and behavioral deficiencies. However, 12 weeks after receiving the ITSCs, the cells had migrated into the animals' brains and functional ability was not only fully restored, but significant behavioral recovery was witnessed, too. In another positive sign, no tumors were found in any of the animals after the transplantations, something that also has been a concern in stem cell therapy.

"Due to their easy accessibility and the resulting possibility of an autologous transplantation approach, ITSCs represent a promising cell source for regenerative medicine," said UB's Barbara Kaltschmidt, Ph.D., who led the study along with Alexander Storch, M.D., and Christiana Ossig, M.D., both of Dresden University. "The lack of ethical concerns associated with human embryonic stem cells is a plus, too."

"In contrast to fighting the symptoms of Parkinson's disease with medications and devices, this research is focused on restoring the dopamine-producing brain cells that are lost during the disease," said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "These cells are easy to access and isolate from nasal tissue, even in older patients, which adds to their attraction as a potential therapeutic tool."

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The full article, "Intrastriatal transplantation of adult human neural crest-derived stem cells improves functional outcome in Parkinsonian rats" can be accessed at http://www.StemCellsTM.com.

http://www.digitaljournal.com/pr/2380610

https://nwpf.org/stay-informed/news/2014/12/stem-cells-from-adult-nose-tissue/

AMPHETAMINES INCREASE THE RISK OF PARKINSON'S DISEASE

12th December 2014 - New research

Previous neurotoxicity findings raised concerns that Amphetamines and Methamphetamines might damage dopaminergic neurons, resulting in dopamine-related medical disorders such as Parkinson's Disease. However, despite widespread use of methamphetamines and other amphetamine type stimulants little was known about the long-term medical consequences of

their abuse and dependence.

A retrospective design was used to examine medical records from 1996 until 2011. Patients were divided between (1) Amphetamine and Methamphetamine users, (2) Cocaine users, (3) those people that have not been exposed to drugs or alcohol. They were assessed to see if they were at an increased risk of developing either (1) Parkinson's Disease, or (2) Parkinson's Disease / Parkinsonism / Essential Tremor when compared to people that did not take drugs.

In Methamphetamine and Amphetamine users there was a nearly three fold increased risk of Parkinson's Disease, thereby indicating them as a cause of Parkinson's Disease. However, Cocaine users did not show any elevated risk of Parkinson's Disease.

The increased likelihood of developing Parkinson's Disease probably occurs because of the long term effect of amphetamines on the dopamine receptors, which they affect.

Reference : Drug and Alcohol Dependence [2014] Nov 16 [Epub ahead of print] (K.Curtin,

A.E.Fleckenstein, R.J.Robison, M.J.Crookston, K.R.Smith, G.R.Hanson)

http://www.viartis.net/parkinsons.disease/news/141212.pdf

mail@viartis.net

GUT CHECK ON PARKINSON’S: NEW FINDINGS ON BACTERIA LEVELS

Wednesday, 10 December 2014

“Listen to your gut” is common advice when faced with an important decision. Researchers are now heeding these words to gain further insights into Parkinson’s disease (PD).

The human digestive tract contains up to a thousand different types of bacteria, which help you digest  food, make vitamins and maintain your immune system. The amount of bacteria is influenced by diet, age and other variables, and is thus unique to each individual.

Filip Scheperjans, MD, PhD, and colleagues from the University of Helsinki, Finland examined the intestinal contents of 72 people with Parkinson’s and 72 without PD. Their research, funded by MJFF and published recently in Movement Disorders, revealed that people with Parkinson’s had lower levels of a certain bacterium and that concentrations of another bacterium varied among subgroups of those with PD with differing motor symptoms.

Intestines as a Window to the Brain

There is a clear effect of Parkinson’s disease on the gastrointestinal system. Nearly 80 percent of people with PD have constipation, and this condition often predates the motor symptoms of Parkinson’s by several years.

Additionally, alpha-synuclein — a protein that clumps in the brains of all people with Parkinson’s — has been found in several locations outside the brain, including the nerves controlling the intestines. Investigators question whether the abnormal protein could show up here first, causing non-motor symptoms, and later spread to the brain to cause motor symptoms.

Lastly, researchers believe the normal bacteria of the gut might affect the functioning of the gut nerves which could in turn affect the nerves of the brain.

Specific Bacterial Levels Are Affected in Parkinson’s Disease 

In Dr. Scheperjans’ study, the bacteria Prevotella was present at lower levels in the guts of people with Parkinson’s disease. This bacterium aids in the creation of the vitamins thiamine and folate and the maintenance of an intestinal barrier protecting against environmental toxins. This finding may therefore have implications not only for diagnosis but also for dietary adjustments or vitamin supplementation for management of PD in the future.

In people with Parkinson’s with more severe postural instability and gait difficulty, as opposed to tremor, the bacterium Enterobacteria was present at higher levels. The reasons for this association were not clear.

Studying Intestinal Bacteria Will Advance Understanding of Parkinson’s

Deciphering information from the gut could lead to earlier and more definitive diagnosis, a better understanding of how Parkinson’s progresses, and ways to separate the populations of people with differing symptoms of PD.

If researchers determine that there are specific and consistent differences in the gut, bacteria may serve as biomarkers — objective measurements to diagnose or track PD. As the gut is much more accessible than the brain and can be analyzed through stool samples, a bacterial biomarker is an attractive prospect.

Additionally, we don’t know why people with Parkinson’s disease show such varied motor symptoms (gait problems versus tremor, for example) or who will get which. Bacterial differences may allow us to separate the subtypes of Parkinson’s and, as a result, give individuals a better idea of the symptoms and disease progression they might expect.

More Research Is Needed

Further studies are called for to learn more about the relationship between these and other gut bacteria and Parkinson’s. In the meantime, researchers are intensely studying alpha-synuclein to determine how and why this protein contributes to Parkinson’s, and its connection between the gut and the brain.

Until a disease-modifying therapy is found, symptomatic treatments, including a drug for constipation, remain under development.

Article Source:   The Michael J. Fox Foundation for Parkinson’s research

Parkinson's Vaccine Being Tested on Patients in Europe

The EU-consortium SYMPATH started recruitment for a Phase 1 study of a Parkinson's vaccine candidate called AFFITOPE PD03A. This vaccine is one out of a designated pool of promising vaccine candidates based on AFFiRiS' proprietary affitope technology. These candidates aim at disease modification of Parkinson's instead of only ameliorating the severe motor symptoms of the disease, such as tremor. All vaccines in this pool target alpha-Synuclein, a protein that is key to the onset and the progression of both, Parkinson's and multiple system atrophy (MSA). Recently, encouraging clinical results of a Parkinson's trial of one other of the pool's vaccines, namely PD01A, were presented by the Michael J. Fox Foundation and AFFiRiS. These confirmed the safety and tolerability of the vaccine, as well as its ability to induce an immune response and even achieve functional stabilization.

Commenting on the latest clinical trial, Prof. Achim Schneeberger, Chief Medical Officer at AFFiRiS and coordinator of SYMPATH, explains: "The results we achieved with the Parkinson's vaccine PD01A were very encouraging. Now, PD03A will be tested in a comparable setting and we are eagerly awaiting the results. "The current trial of PD03A is a multi-centric patient blinded, randomized, placebo-controlled, parallel group Phase 1 trial. It will be conducted in Vienna and Innsbruck, Austria. Prof. Werner Poewe, chairman of the Department of Neurology at the Medical University of Innsbruck and principal investigator of the study, explains the objectives of the trial: "The primary endpoint of the trial aims to demonstrate the safety and tolerability of the vaccine. It will also assess the vaccine's immunological and clinical activity in vaccinated patients as its secondary endpoint."

Dr. Dieter Volc of PROSENEX Ambulatorium BetriebsgmbH, leading the trial in Vienna, adds: "PD03A is one of the first medications worldwide aiming for clinical efficacy by modulating the metabolic pathway of alpha-Synuclein. It has the potential to treat the cause of Parkinson's – not just the symptoms." Current scientific understanding is that Parkinson's – as well as MSA – is caused by deposits of pathological forms of alpha-Synuclein in the nervous system. The reduction of pathological alpha-Synuclein levels is believed to have a beneficial impact on the progress of the diseases. PD03A aims to accomplish this by inducing the production of antibodies that target and promote clearance of alpha-Synuclein in order to neutralize its toxic impact.

The start of the clinical trial comes only a year after the SYMPATH-Consortium was launched. This rapid progress is owed to the high expertise in Parkinson's and related diseases of all members of the consortium including the Forschungszentrum Jülich in Germany, the INSERM F-CRIN Toulouse, the Departments of Neurology at the University Hospitals of Bordeaux and Toulouse, France, as well as the Medical University of Innsbruck's Department of Neurology and PROSENEX, Vienna, Austria. Additionally, the successful track record of the AFFiRiS affitome platform that forms the basis of PD01A and PD03A significantly accelerated the vaccine development. Dr. Markus Mandler, head of the Neurodegeneration Department at AFFiRiS explains: "Both vaccines are based on AFFiRiS' affitome technology. This technology delivers not only a single vaccine for the treatment of a certain disease but a whole pool of product candidates with excellent safety profiles and strong specificity to their targets."

Source: Affiris AG

http://health.einnews.com/article/238853225/RmiEEUxyfQjup0WU

Parkinson's disease sufferers win payout from Pfizer for drug linked to gambling, sex addiction

By Kate Hagan

Dec. 8, 2014, 4:42 p.m.

Almost 200 Australians who developed gambling and sexual addictions after taking prescription drugs used to treat Parkinson's disease will be awarded compensation over alleged failures to warn them about side-effects.

Drug manufacturer Pfizer this month agreed to settle with 160 Australians who took its drug Cabaser to treat tremors associated with Parkinson's disease or restless legs syndrome between 1996 and 2010.

The agreement, ahead of a class action due to be heard in the Federal Court, follows a settlement last year for 32 people in a similar action against Aspen Pharmacare and Eli Lilly over their drug Permax.

Patients are expected to share in millions of dollars' compensation, with some losing hundreds of thousands of dollars on gambling binges after taking the drugs despite not having prior gambling problems.

Both Parkinson's disease and restless legs syndrome are neurological disorders caused by a lack of dopamine in the brain.

"Dopamine agonists" mimic the effects of dopamine, in some cases restoring a person's ability to control their movements.

But the chemical is also known to produce a "rush" which has been linked to risk-taking behaviours and addictions.

The class actions alleged that drug companies were negligent in selling the medicines in Australia without any or adequate warnings about side-effects.

Arnold Thomas & Becker partner Allanah Goodwin said this led people to go on "gambling and shopping binges and engage in bizarre hypersexual behaviour, without realising it was a side effect" of the medicines.

Clients who developed gambling addictions ranged from "a pensioner who might have lost a modest sum to professionals who had a lot more money to go through," she said.

Pat Galea, 65, lost about $700,000 on poker machines after taking both Permax and Cabaser for about a decade for restless legs syndrome, which creates an urge for sufferers to move their legs.

"I'd go any spare moment I was not working. If it was pay day I'd put most of it through and then realise I've got bills and rent and petrol to pay. As soon as I had any money it was gone," Mrs Galea said.

She separated from her husband and gambled away half the proceeds from the sale of their house, also selling her car to fund her addiction

It took years for evidence to emerge about the drugs' side-effects and as soon as Mrs Galea stopped taking them, she lost the urge to gamble.

She has since reunited with her husband and enjoys time with her three adult children and four grandchildren. Asked whether the settlement came close to repaying what was lost, she laughed.

"It's a drop in the bucket. And that's just the money. What about years of life for my family? What about their suffering, let alone me?" she said.

Salvation Army financial counsellor Maria Turnbull was among the first to ask questions about a link between dopamine agonists and compulsive gambling after a bankrupt woman in her 60s came to her seeking food vouchers in 2006.

The woman told Mrs Turnbull that drugs she was taking for restless legs syndrome had led her to gamble, and she started looking into a possible link.

Mrs Turnbull has since met more than 100 people involved in the Australian class actions, including a man who developed compulsive sexual behaviour and is now on the sex offenders register. He needs permission to see his grandchildren.

"There are people I'm sure who have committed suicide over this. They haven't known it was the drug doing it. There are families that have been ripped apart," she said.

A spokeswoman for Pfizer Australia said that while the parties had agreed on a proposed settlement, this was subject to Federal Court approval, and the drug company was therefore unable to provide further comment.

The story Parkinson's disease sufferers win payout from Pfizer for drug linked to gambling, sex addiction first appeared on The Sydney Morning Herald.

http://www.camdencourier.com.au/story/2750439/parkinsons-disease-sufferers-win-payout-from-pfizer-for-drug-linked-to-gambling-sex-addiction/?cs=7