On Parkinson’s trail

June 3, 2018   Sunderarajan Padmanabhan

Scientists at a Kolkata institute find new clues to its cause

Despite research spread over decades, scientists are yet to figure out the cause for Parkinson’s disease, a neurodegenerative disorder. One thing is clear: the aggregation of a protein called alpha-synuclein plays a key role in development of the disease. The aggregation pathway of this protein is the subject of intense research and studies so far have focussed on protein aggregates, called amyloid fibrils, which form late in the aggregation pathway.

Researchers at the CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata, have now proposed that alpha-synuclein oligomers that come into the picture early in the aggregation pathway could be responsible for the development of Parkinson’s.

They used two amino acids to conduct their study in live neuroblastoma cells. The first one was glutamate, which happens to assist the formation of amyloid fibrils by facilitating generation of early oligomers. The second one was arginine, which inhibits amyloid fibril formation by inducing a large change in the shape of the native protein.

The study has shown that it is possible to monitor early events of the aggregation pathway when the native protein fluctuates in its monomeric states or when it forms early oligomeric molecules by using a combination of conventional methods and spectroscopy at the single molecule level.

“We have shown that it is possible to monitor and understand the early events in aggregation. It gives us hope that a therapeutic molecule may be possible against early oligomeric molecules,” says Dr. Krishnananda Chattopadhyay, leader of the research team.

“The study establishes that glutamate acts as a facilitator and arginine acts as an inhibitor of the late stage of alpha synuclein aggregation. However, it is not clear if the observed effect is because of other cellular changes due to the addition of these molecules or direct interaction of these molecules with alpha-synuclein. The mechanism of internalisation and interaction of these molecules with alpha-synuclein needs to be better understood. It will also be challenging to understand how one can transform this knowledge for drug development for a complex disease such as Parkinson’s,” says Dr. Samir K. Maji of IIT Bombay, who was not connected with the study.

Other researchers in the study included Sumanta Ghosh and Amrita Kundu of the CSIR-ICB. The research results have been published in the journal, Scientific Reports, and the work was funded by the Department of Science and Technology, Government of India. 

— India Science Wire

http://www.thehindu.com/sci-tech/health/on-parkinsons-trail/article24069288.ece

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Parkinson's: 'Adaptive' brain implant may improve therapy

By Maria Cohut   June 2, 2018

An adjustable new brain stimulation implant could bring Parkinson's therapy to a whole new level.

Parkinson's, a neurodegenerative condition, is characterized by symptoms such as muscle stiffness and tremor in the limbs, as well as impaired balance, all of which tend to worsen over time. Has innovative research found a more reliable tool that helps to improve these symptoms?

The National Institutes of Health (NIH) report that approximately 50,000 individuals in the United States receive a Parkinson's diseasediagnosis every year.

Available treatments for this condition target its symptoms, aiming to improve the patients' quality of life.

These treatments include different types of drugs that may focus either on motor on non-motor effects of the disease, as well as deep brain stimulation, which may be offered as an alternative therapy to people who do not respond well to drugs.

In deep brain stimulation, electrodes are surgically implanted into the brain. These are connected to a device that is attached to the chest. Through these implants, electrical stimuli are transmitted to the regions of the brain that regulate movement.

However, deep brain stimulation has — at least so far — come with certain risks and drawbacks. The device works continuously and has to be programmed so that the stimuli it sends are best adjusted to the wearer's needs.

Often, devices will need to be reprogrammed by a specialist. Also, because they run on batteries, the lifespan of these implants is limited, and they eventually have to be replaced.

A team from the National Institute of Neurological Disorders and Stroke — led by specialist Nick B. Langhals — recognizes these drawbacks and set out to test more personalizable deep brain stimulation implants.

The results of their efforts — which were part of the Advancing Innovative Technologies (BRAIN) Initiative — have been reported in the Journal of Neural Engineering.

A new type of brain stimulation implant

Langhals and team tested a type of implant that responds and adjusts to signals from the brain that are related to the symptoms experienced in Parkinson's disease. Not only does it register these inputs, but in doing so, it also adapts to deliver appropriate stimulation as needed.

"This is the first time," explains senior study author Dr. Philip Starr, that "a fully implanted device has been used for closed-loop [non-constant], adaptive deep brain stimulation in human Parkinson's disease patients."

The project was a short-term feasibility trial, in which two people with Parkinson's agreed to receive this fine-tuned, adaptable deep brain stimulation implant.

In this trial, the implant was programmed to monitor the brain for signals related to dyskinesia — or involuntary movements — which sometimes occurs as a side effect of deep brain stimulation.

So, when the device picked up signs of dyskinesia, it reduced stimulation to the brain. On the other hand, when no dyskinesia was detected, the stimulation was increased. This strategy was calculated to decrease the side effects related to this type of therapy.

The trial's results indicated that this type of implant was no less effective in reducing Parkinson's symptoms than traditional deep brain stimulation.

Also, since this device is adaptive and does not send out stimuli constantly, the researchers noted that it saves approximately 40 percent of the battery energy that would normally be consumed during traditional, open-loop brain stimulation.

Because these tests were only carried out over a short period of time, it was not possible for the investigators to establish exactly how the innovative implant performed, compared with more traditional brain stimulation devices, when it comes to instances of dyskinesia.

However, due to the new implant's adaptability, the researchers are hopeful that the closed-loop stimulation device would fare much better in this respect and possibly lead to fewer adverse effects.

'An important first step'

Also, Dr. Starr explains, "Other adaptive deep brain stimulation designs record brain activity from an area adjacent to where the stimulation occurs, in the basal ganglia, which is susceptible to interference from stimulation current."

"Instead," he goes on, "our device receives feedback from the motor cortex, far from the stimulation source, providing a more reliable signal."

The researchers are excited about the avenues that this feasibility study is opening up in terms of improving Parkinson's therapy, and they are already planning larger trials in order to test the device's long-term effectiveness.

"

The novel approach taken in this small-scale feasibility study may be an important first step in developing a more refined or personalized way for doctors to reduce the problems patients with Parkinson's disease face every day."

Nick B. Langhals

You can watch the lead researcher's explanation about the innovative brain stimulation devices in the video below.

https://youtu.be/eID5y3UqrGA

https://www.medicalnewstoday.com/articles/322003.php

Investigating fungi: A new frontier in Parkinson’s disease

June 1, 2018

Dr. Silke Cresswell

For researchers who study Parkinson’s disease, a new frontier of investigation is emerging: the micro-organisms, including viruses, bacteria and fungi that live in and on us.

At the University of British Columbia, Dr. Silke Cresswell, a neurologist and assistant professor, is concentrating on changes to the olfactory system and the gut that occur long before the tremor, stiffness and trouble walking that are the classic motor symptoms of Parkinson’s. Her latest project is being funded by the Parkinson Society of British Columbia with a one-year, $44,996 Pilot Project Grant from the Parkinson Canada Research Program.

Loss of the sense of smell, insomnia and constipation are all symptoms that people with Parkinson’s may experience years or even decades before their movement difficulties emerge – but often, clinicians don’t link the issues.

“If you look at the pathology, you can see pathological changes in the nervous system of the gut very early on,” Cresswell says.

Cresswell and her colleagues know that the internal surface of the nose and the entire gut are heavily populated by microbes that co-exist there and serve as the interface between the environment and the human body.

“It turns out that the microbes outnumber the number of cells that are human by a factor of 100,” she says. “We have more microbes in our system than human cells.”

Cresswell now wonders if the fungi in the gut influence the development of Parkinson’s disease. Using fecal and nasal samples from people who have Parkinson’s and people who do not, she is assessing those samples to see if changes in the fungi could be related to Parkinson’s and its symptoms ranging from tremor and rigidity to constipation, depression and impaired judgment and reasoning.

If Cresswell can establish a relationship between fungi and the symptoms of Parkinson’s disease, her work would open the door for follow-up studies to examine the mechanisms by which fungi might influence the development of Parkinson’s disease. This line of research might eventually lead to treating the fungi with antifungal medications, for example, to see if eliminating the fungus or reducing the amount of it in the body also eliminates Parkinson’s.

Alternatively, it might also be possible to boost other microbes in the body, such as with probiotics.

“The really exciting thing would be if in the future, we could look at people at high risk of Parkinson’s and treat them early,” she says.

Identifying what role the human microbiome plays in disease is truly a new frontier for medicine, Cresswell says.

“It is something that is easily accessible and modifiable, so it holds promise for treatment.”

Read about other researchers recently funded by the Parkinson Canada Research Program by visiting the research section of www.parkinson.ca.

http://parkinsonpost.com/investigating-fungi-a-new-frontier-in-parkinsons-disease/

Previous ArticleNext Article Enzyme plays key role in Parkinson’s disease and inflammation

June 1, 2018

From left, Jun Yang, Ph.D., and Sung Hee Hwang, Ph.D., who work in the lab of Hammock, are with the UCD Department of Entomology and Nematology and the UCD Comprehensive Cancer Center. (Photo courtesy of Kathy Keatley Garvey)

New research partially funded by NIEHS suggests an enzyme in the brain plays a key role in Parkinson’s disease (PD). Scientists demonstrated that inhibiting an enzyme known as soluble epoxide hydrolase (sEH) can help curb the inflammation associated with the development and progression of PD.

The team from the University of California-Davis (UCD), worked closely with colleagues in Japan and China. Their research appeared May 7 in the Proceedings of the National Academy of Sciences.

The project was led by Kenji Hashimoto, Ph.D., at Chiba University Center for Forensic Mental Health in Japan, and Bruce Hammock, Ph.D., from UCD. Hammock is a longtime NIEHS grantee and directs the NIEHS-funded Superfund Research Program (SRP) at UCD.

Key regulatory enzyme

Hammock explained that sEH is a key regulatory enzyme involved in the metabolism of fatty acids. “[In] our previous research, we found that sEH inhibitors treat neuropathic and inflammatory pain in humans and companion animals,” he said. “Now we're finding that these inhibitors play a key role in Parkinson's disease.”

In studies involving mice, the scientists found that sEH plays an important role in the inflammation associated with both progression of PD and the mechanisms that lead to the disease. They tested a potent sEH inhibitor and a mouse model that was genetically modified not to produce sEH. The two approaches produced similar results.

“By establishing this causal chain of events … we can better predict environmental chemicals that could predispose people to Parkinson's disease and possibly even treat the disease,” Hammock suggested.

sEH plays an important role in the inflammation associated with both progression of PD and the mechanisms that lead to the disease. 

Bruce Hammock and collaborators

“The Hammock lab studied foreign compound metabolism, which led to the work on the role of epoxide hydrolases in pain and inflammation,” noted Heather Henry, Ph.D., from the NIEHS Hazardous Substances Branch. “Now, 30 years into research at the UC Davis SRP, they report its potential role in reducing inflammation in Parkinson’s. It seems this is only the beginning of understanding how broadly applicable their discoveries are.”

Therapeutic target

“[Both] the sEH inhibitor [and] deletion of the sEH gene protected against MPTP-induced neurotoxicity in mouse brain,” Hashimoto said. MPTP is a relative of cyperquat and paraquat herbicides.

Hashimoto pointed out that medications to treat PD symptoms do not prevent the progression of the disease. “Therefore, the development of new drugs possessing disease-modifying or neuroprotective properties is critical,” he said.

sHE implicated in cell death

“While we know that a certain group of brain cells that produce dopamine are selectively destroyed in Parkinson's patients, what triggers this brain cell death remains poorly understood,” said Cesar Borlongan, Ph.D.,  from the University of South Florida. Borlongan was not involved in the study.

sEH inhibitors will soon enter human clinical trials. 

Bruce Hammock

“In small and large animal models of Parkinson's disease, and further confirmed in a group of PD patients, [sEH] is highly elevated in specific regions of the brain implicated in dopamine cell death,” he observed.

The authors reported that the enzyme was also highly expressed in the brains of patients with a disease called dementia of Lewy bodies. That form of dementia, like PD, involves deposits of a protein called alpha-synuclein, in multiple regions of the brain.

Clinical trials

According to Hammock, sEH inhibitors will soon enter human clinical trials supported by the Blueprint Program of the National Institute of Neurological Disorders and Stroke. “These drugs could provide relief for patients with a wide variety of inflammatory diseases,” he suggested. Hammock is CEO of a Davis-based company, EicOsis, that is developing the sEH inhibitors.

“sEH can break down some of the natural fatty acids in the body that reduce inflammation, high blood pressure, and pain symptoms,” explained Daniel Shaughnessy, Ph.D., from NIEHS. “Bruce and his colleague Alan Buckpitt [Ph.D.] saw the potential of inhibiting sEH as therapy for inflammation-related conditions.”

The researchers received a Small Business Innovation Research (SBIR) grant from NIEHS to develop sEH inhibitors for treating neuropathic pain. Shaughnessy is the NIEHS program lead for SBIR grants.

Citation: Ren Q, Ma M, Yang J, Nonaka R, Yamaguchi A, Ishikawa KI, Kobayashi K, Murayama S, Hwang SH, Saiki S, Akamatsu W, Hattori N, Hammock BD, Hashimoto K. 2018. Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson's disease. Proc Natl Acad Sci U S A; doi:10.1073/pnas.1802179115 [Online 7 May 2018].

(This story is based on a UCD press release by Kathy Keatley Garvey.)

https://factor.niehs.nih.gov/2018/6/papers/parkinsons/index.htm

Man Blames Dow Solvent for His Parkinson’s Disease

Contributing Editor     June 1, 2018

A man who worked for 18 years as an electronic journeyman at Boeing Corp.’s Torrance plant is suing Dow Chemical Co., alleging his longtime exposure to a Dow cleaning solvent caused him to get Parkinson’s disease.

A Dow representative could not be immediately reached for comment on Daniel O’Leary’s Los Angeles Superior Court lawsuit, which alleges negligence, fraud and strict liability. His wife and co-plaintiff, Darla O’Leary, alleges loss of consortium in the complaint brought Thursday, and they are seeking unspecified damages.

Boeing Corp. is not being sued.

O’Leary was employed at a machine shop at the Boeing plant from February 1982 until September 2000 and during that time, worked on electronic machine parts and used various solvents, according to the complaint.

In the 1990s, Boeing began using a degreaser called NEU-TRI that contained trichloroethylene, also known as TCE, the suit states. TCE, a chemical compound and halocarbon commonly used as an industrial solvent, has been been the subject of numerous groundwater-contamination lawsuits.

Throughout his time at Boeing, O’Leary was required to buy NEU-TRI from Dow so it could be used on Boeing electrical parts and motors, his suit states. He was exposed to NEU-TRI daily from minutes to several hours daily, according to the complaint.

O’Leary ultimately developed Parkinson’s disease in June 2011 as well as other illnesses due to the exposure for which he requires constant care, according to his lawsuit. He learned in June 2016 that his health problems could be related to his work at Boeing, the suit says.

O’Leary alleges Dow failed to disclose to him and to Boeing that NEU-TRI contained TCE, which was known to cause Parkinson’s disease.

https://mynewsla.com/crime/2018/06/01/man-blames-dow-solvent-for-his-parkinsons-disease/

Parkinson's disease research gets $240k boost

AARON LEAMAN  June 1 2018

Auckland University Associate Professor in Anatomy Maurice Curtis said the grant from the Livingstone Estate would help progress research into Parkinson's disease.

New Zealand-based research into potential treatments for Parkinson's disease has been given a six-figure funding boost.

The Livingstone Estate has donated $240,000 to the Neuro Research Charitable Trust (NRCT) to help progress the discovery of drugs to combat the disease.

Levodopa, the main drug used to treat Parkinson's, dates to the 1970s and doesn't slow the disease's progression.

John Dobson, a trustee for the Livingstone Estate, has made a $240,000 donation to the Neuro Research Charitable Trust (file photo).

The NRCT, which was founded by Hamilton businessman Bernie Crosby, has been working in partnership with Auckland University to study the earliest changes that occur in the brain as a result of Parkinson's disease.

To date, that work has revealed how Parkinson's can spread from cell to cell in cultured human brain cells.

Livingstone Estate trustee John Dobson said the $240,000 donation brought the estate's total contribution to the NRCT to $540,000 and helped honour the wishes of his late aunt, Margaret Livingstone.

That $540,000 will go toward the NRCT's pledge of $900,000 over three years to the Centre for Brain Research based at Auckland University. Livingstone died in 2016 and left her estate to medical research.

Margaret Livingstone spent the last years of her life in Hamilton.

Dobson said he was inspired after visiting the Centre for Brain Research.

"Since Aunty Margaret didn't have children, she wanted to make sure that her hard-earned money went to a really good cause. After looking around, I couldn't find anything better than the Centre for Brain Research and what they're doing," Dobson said.

The Livingstone Estate's initial $300,000 donation is being used to help accelerate research into ways to slow down or prevent the cellular spread of Lewy bodies, the pathological protein that causes Parkinson's disease.

The additional $240,000 will be used to progress the discovery of new drug treatments.

"I'm sort of an impatient type of guy. I like things to happen quickly," Dobson said.

"Research seems to be moving forward, but I want to see a solution. When I found out that further funding could progress the discovery of a drug, I decided to add another $240,000."

Auckland University Associate Professor in Anatomy Maurice Curtis said research by the Centre for Brain Research was being carried out using human brain tissue.

"We're able to grow cells from the brains of people who donated their brains to the brain bank at Auckland University ... to see how Parkinson's cells differ from normal cells," Curtis said.

"We can use those cells that are transferring Lewy bodies and test drugs on them."

Curtis said researchers' ultimate goal is to develop a drug which slows down or stops the spread of Lewy bodies. Part of that goal is to allow early intervention.

Parkinson's disease is caused by the loss of dopamine-producing cells in the region of the brain known as the substantia nigra.

Currently, the treatment for Parkinson's happens late. It can be six to 10 years after the brain has been affected before a person shows the overt symptoms of Parkinson's: movement disorders, difficulties in ordering their day, and sometimes confusion.

"That's why we are interested to find out where in the brain is affected first and what those brain changes are," Curtis said.

"We know that Lewy bodies show up early on in the olfactory bulb, which is the area of the brain that allows us a sense of smell. The problem is, we don't know all the mechanisms by which the Lewy bodies spread. That's part of the research project: understanding how these Lewy bodies are being spread. If we can slow that process, we believe it can lead to better outcomes."

Bringing a new drug on to the market takes 10 to 15 years. It's possible that an existing drug could be repurposed and be made available much sooner.

"With research, none of the knowledge is ever wasted," Curtis said.

"It's a case of the global community working together to understand what actually is going wrong in Parkinson's disease."

https://www.stuff.co.nz/national/health/104331567/parkinsons-disease-research-gets-240k-boost

Smart app to diagnose Parkinson's disease

June 1, 2018, CORDIS

Parkinson's disease (PD) is a slow, progressive disorder of the central nervous system affecting between 7 and 10 million people worldwide. In Europe, there are 1.2 million people living with the disease, most of them over 50. PD develops gradually over time and early signs are so subtle that they often go unnoticed. Although we know that some symptoms set in years before the disease is diagnosed, there's no specific way to detect PD early on.

Keeping in mind the significant benefits of early detection, patients, doctors and engineers joined forces to find a solution in the EU-funded project i-PROGNOSIS. Coordinated by the Aristotle University of Thessaloniki, Greece, the four-year project is developing a set of technology-based solutions for the early detection and care of the disease. 

The i-PROGNOSIS approach is based on the unobtrusive collection of behavioural data obtained from users' natural interaction with their smart devices. The aim is to capture data that may be linked to early PD symptoms.

With this goal in mind, in 2017 the team launched the iPrognosis mobile application (available for free on the Google Play Store) in Germany, Greece, Portugal and the United Kingdom. According to a news release on the project website, more than 740 Europeans have downloaded the app on their smartphones, smartwatches or fitness bands since its release. 

Feedback to date is very positive. A questionnaire circulated to app users confirms the project partners' initial findings that the app doesn't change a smartphone's normal operation. Users also reported needing little assistance to set up and use the app. They consider it a useful tool in early PD detection research.

How does the app work?

Following user consent, the app collects a wide variety of data: voice characteristics while users are talking on the phone, hand steadiness while they're holding the device and keystrokes-related data when using the app's keyboard. Other information is also gathered about distance covered each day, facial expressions from stored photos and emotional content from stored text messages. 

User privacy is protected by encrypting data and replacing the user's name with a coded ID. Users don't need to change anything about the way they use their smartphones. They can go on making and receiving calls, typing messages and taking photos as they usually do.

Smartwatches and bands have additional advantages. Since they're worn for long periods of time – unlike phones that are usually left lying somewhere – they're able to capture more data on physical activity. The devices' heart rate and skin temperature sensors can also be used to monitor sleep quality, since sleep disorders are an early symptom of PD.

So far, around 433 625 records – about 90 GB of data – have been collected. The data is being used to develop machine-learning algorithms that can detect PD-related behavioural changes. The project partners are now starting to medically evaluate the first version of these algorithms. When the gathered data points to PD-related behaviour, users are asked to visit a doctor. They can then choose to go on to the second stage of detection.

What comes next?

i-PROGNOSIS (Intelligent Parkinson eaRly detectiOn Guiding NOvel Supportive InterventionS) is focusing on capturing additional data that may relate to early PD symptoms. The everyday smart utilities it will be using in this stage are plate scales, smart belts and smart TV remote controls to collect data on food consumption rates, bowel sounds and heart rates, respectively. Ultimately, i-PROGNOSIS plans to design interventions to help Parkinson's patients sustain their quality of life, in collaboration with their doctors.

More information: For more information, see www.i-prognosis.eu/ 

Provided by: CORDIS 

https://phys.org/news/2018-06-smart-app-parkinson-disease.htmlhttps://phys.org/news/2018-06-smart-app-parkinson-disease.html

Parkinson’s Disease Shares Brainwave Abnormalities with Other Neurological Disorders, Study Finds

JUNE 1, 2018 BY ALICE MELÃO 

An abnormal brain activity pattern could be a common link between Parkinson’s disease, neuropathic pain, tinnitus, and depression, an international research team suggests.

The brainwave abnormality is similar in all these disorders but occurs in different regions of the brain. This discovery could lead to therapies that target all four conditions, the investigators said.

Findings were published in the study, “Thalamocortical dysrhythmia detected by machine learning,” in the journal Nature Communications.

Whether a person is awake or asleep, moving or thinking, the brain produces specific brainwave patterns that represent, to some extent, how the brain works.

Researchers proposed, back in 1996, that specific oscillations in these brainwaves could be common to several neurological diseases, including Parkinson’s. This theory — called thalamocortical dysrhythmia, or TCD — suggests that patients with these conditions have a drop in brainwave frequency in neurons of the thalamus, and alpha waves are replaced by theta waves.

Alpha waves inhibit other neurons in the thalamus from firing, having a sort of muting effect in the brain. The loss of these waves allows neighboring cells to be more active, and the thalamus becomes hyperactive.

To confirm the TCD hypothesis, Sven Vanneste, PhD, an associate professor in the School of Behavioral and Brain Sciences at the University of Texas at Dallas, and his colleagues used a computer-based approach to map the major brainwave patterns of people with Parkinson’s, neuropathic pain, tinnitus — the perception of ringing or buzzing in the ears — and depression.

The study included 541 individuals, including 264 healthy volunteers, 153 patients with tinnitus, 78 with chronic pain, 31 with Parkinson’s, and 15 with major depression.

Using electroencephalography (EEG) data, the computer model revealed that all patients had equivalent changes in brainwave activity. However, depending on the disease, these alterations appeared in different regions of the brain.

For patients with tinnitus, brainwave abnormalities were identified in the auditory cortex, whereas chronic pain patients had these disruptions in the somatosensory cortex. Parkinson’s disease affected the motor cortex, and depression patients had brainwave abnormalities in deeper brain layers.

“We fed all the data into the computer model, which picked up the brain signals that TCD says would predict if someone has a particular disorder,” Vanneste said in a university news article. “Not only did the program provide the results TCD predicted, we also added a spatial feature to it. Depending on the disease, different areas of the brain become involved.”

While more studies are needed to validate these results, the findings seem to validate “TCD as oscillatory mechanism underlying diverse neurological disorders,” the investigators wrote in the study.

“Over the past 20 years, there have been pain researchers observing a pattern for pain, or tinnitus researchers doing the same for tinnitus,” Vanneste said. “But no one combined the different disorders to say, ‘What’s the difference between these diseases in terms of brainwaves, and what do they have in common?’ The strength of our paper is that we have a large enough data sample to show that TCD could be an explanation for several neurological diseases.”

The team is now planning to investigate brainwave abnormalities in other psychiatric diseases and to explore the therapeutic potential of vagus nerve stimulation as a means to reset these brainwave patterns. The approach is being developed by Vanneste and colleagues at the Texas Biomedical Device Center, UT Dallas.

“More and more people agree that something like thalamocortical dysrhythmia exists,” Vanneste said. “From here, we hope to stimulate specific brain areas involved in these diseases … to normalize the brainwaves again. We have a rationale that we believe will make this type of therapy work.”

https://parkinsonsnewstoday.com/2018/06/01/common-abnormal-brainwave-pattern-links-parkinsons-other-disorders-study/

Synaptic Vesicle Defect Leads to Neurodegeneration in Parkinson’s, Study Suggests

JUNE 1, 2018 BY JOSE MARQUES LOPES, PHD IN NEWS.

Impaired intake of neurotransmitters leads to accumulation of toxic dopamine and neurodegeneration in patients with Parkinson’s disease, according to a new Northwestern Medicine study.

The study, “LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease,” appeared in the journal Proceedings of the National Academy of Sciences.

Parkinson’s is characterized by a substantial loss of neurons that produce the neurotransmitter dopamine in a brain area called substantia nigra. Prior research conducted by a team led by Dimitri Krainc, MD, PhD, chair and Aaron Montgomery Ward Professor of Neurology at Northwestern, showed that the accumulation of oxidized dopamine in the brain regulates the death of these neurons, which leads to Parkinson’s motor symptoms.

In neurons, neurotransmitters are stored in tiny vesicles near the synapse. Scientists have recently found genes associated with Parkinson’s involved in the transport of vesicles from these synaptic terminals toward the cell’s interior, a process called endocytosis. Through endocytosis, neurons replenish the levels of neurotransmitters to enable continued communication.

This discovery supported the importance of impaired neuronal communication, or synaptic dysfunction, in disease development, but the precise mechanisms leading to neuronal death remained unknown.

“In this paper, we further explain how such oxidized dopamine is formed in synaptic terminals of neurons from patients with Parkinson’s,” Krainc, the study’s senior author, said in a press release.

Results showed that a mutated form of the Parkinson’s-associated enzyme LRRK2dysregulates auxilin, a protein normally responsible for synaptic vesicle endocytosis. This led to faulty endocytosis and decreased density of vesicles in patient-derived dopaminergic neurons.

Importantly, the scientists also observed that impaired endocytosis led to accumulation of oxidized dopamine in neurons. In turn, this buildup of toxic dopamine caused Parkinson’s-related effects, including an increase in alpha-synuclein, the main component of protein clumps called Lewy bodies.

“Together, this work suggests that mutant LRRK2 disrupts synaptic vesicle endocytosis, leading to altered dopamine metabolism and dopamine-mediated toxic effects in patient-derived dopaminergic neurons,” the investigators wrote in the study.

“These findings suggest that early therapeutic intervention in dysfunctional presynaptic terminals may prevent downstream toxic effects of oxidized dopamine and neurodegeneration in [Parkinson’s],” Krainc said in the release.

Additionally, investigating genetic forms of Parkinson’s contributes to increased understanding of key cellular mechanisms in the development of the disease, the researchers noted.

“This study is another example of how the emergence of genetic causes of Parkinson’s has helped us understand how disease develops and where to focus to identify key pathways and targets for drug development,” Krainc said.

https://parkinsonsnewstoday.com/2018/06/01/synaptic-vesicle-defect-precedes-neurodegeneration-parkinsons-study/