Tau prevents synaptic transmission at early stage of neurodegeneration

May 19, 2017

Tau proteins are involved in more than twenty neurodegenerative diseases, including various forms of dementia. These proteins clump together in patients' brains to form neuronal tangles: protein aggregation that eventually coincides with the death of brain cells. Prof. Patrik Verstreken's research team (VIB-KU Leuven) has now discovered how tau disrupts the functioning of nerve cells, even before it starts forming tangles. They immediately suggest a way to intervene in this process.

Tau proteins are best known as the proteins that are stacked to form neuronal "tangles" in Alzheimer's patients' brains, but they also play a role in many other brain disorders such as Parkinson's and Huntington's disease. In healthy circumstances, tau proteins are connected to the cytoskeleton of nerve cells, where they support the cells' structural stability. In the nerve cells of patients, however, tau is dislodged from the cytoskeleton and ultimately tangles together to form protein accumulations that disrupt the nerve cell's functioning.

Early spoilsport

But even before these protein accumulations are formed, the dislodged tau impedes the communication between nerve cells. VIB's research team has described a new mechanism for this in the journal Nature Communications.

Professor Patrik Verstreken (VIB-KU Leuven) explains: "We have demonstrated that when mutant tau dislodges from the cytoskeleton, it mainly settles at the synapses of the nerve cells. This was not only the case in fruit flies and rats but also in the brain cells of human patients. Vesicles containing chemicals are released at these synapses, which serve as the means of communication between two different nerve cells. When tau settles at the synapse, it locks onto the vesicles, inhibiting synaptic transmission."

Fundamental research with prospects for therapeutic applications

These new insights are the result of a close collaboration between different laboratories at VIB, the universities of Leuven, Louvain-la-Neuve (both in Belgium), and Edinburgh (UK), and with researchers from Janssen Pharmaceutica. They pave the way for a possible treatment.

"Now that we know how tau inhibits synaptic transmission, we can look for ways to prevent it." Patrik Verstreken already provided proof of principle: "If we stop tau from locking onto the vesicles in the nerve cells of rats and fruit flies, we can prevent the inhibition of synaptic transmission and also the death of nerve cells." Further research should reveal whether this strategy will also be useful for patients.

 

More information: Lujia Zhou et al, Tau association with synaptic vesicles causes presynaptic dysfunction, Nature Communications (2017). DOI: 10.1038/NCOMMS15295

Journal reference: Nature Communications 

Provided by: VIB (the Flanders Institute for Biotechnology)

https://medicalxpress.com/news/2017-05-tau-synaptic-transmission-early-stage.html

10 Benefits of Having a Service or Therapy Dog When You Have Parkinson’s

 MAY 18, 2017  BY WENDY HENDERSON IN SOCIAL CLIP

Service dogs are typically thought of as necessary companions for the visually impaired, but service and therapy dogs can be a practical solution for people with a variety of chronic illnesses.

As well as being a trusted friend, service dogs can expand owners’ motor abilities, granting them new independence and allowing them to get more out of life. Here are just a few benefits of having a service dog, according to healthfitnessrevolution.com, mira.ca, the Lung Institute, and rover.com.

Wheelchair Assistance

Service dogs can be trained to pull wheelchairs and to help wheelchairs up ramps and onto sidewalks. They can also help their owner move in and out of the wheelchair.

Anxiety Relief

Having a chronic illness can bring about many emotional and mental health problems. The calming nature of service and therapy dogs can help ease anxiety and petting dogs is known to release endorphins and reduce stress.

Retrieve Items

Service dogs can help chronic disease patients by picking up dropped items and fetching items from other rooms, a vital service for someone who may find getting around difficult and painful.

Lowers Blood Pressure and Heart Rate

There is evidence that stroking a dog and sitting next to a dog lowers blood pressure and heart rate. The soothing effects of their body heat may also help with pain relief.

Improved Balance

Walking with a service dog can help people with chronic diseases who have trouble with their balance. The dogs can also help prop their owners in place to prevent falls.

Good Distraction

Looking after a service dog gives people something to focus on other than their illness. It can help patients develop positive routines and force them to get up and go out.

Exercise

Service dogs, like all dogs, need exercise, so having a service dog encourages owners to get some exercise each day.

Attract Attention

If you need help but are unable to draw attention yourself, your service dog will be able to bark loudly to attract attention from passersby or neighbors.

Promote Communication

Dogs have been known to help promote communication and often prompt conversation from strangers when out and about.

Help Around the House

Therapy dogs are able to help people around the house with simple tasks such as answering the doorbell, retrieving medication, opening and closing doors, and switching lights on and off.

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Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

https://parkinsonsnewstoday.com/2017/05/18/10-benefits-service-therapy-dog-parkinsons/

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( On a personal note: My 9 pound service dog, named Spencer, informed me of a small electrical fire in my iron, before it arc and  burned. I have Parkinson's disease and am unable to smell, by alerting me, I was able to unplug the iron and place it in the sink. He can also alert my emergency button if I fall and am unable to get up or if I am unconscious from the fall. My Service dog has been trained and certified by a Licensed Service dog trainer and was prescribed by my MDS., Margaret Swope)

Lysosomal Storage Disorder Genes Linked as Group to Parkinson's Disease

Collins, Thomas R.

Neurology Today:  18 May 2017 - Volume 17 - Issue 10 - p 53–54

doi: 10.1097/01.NT.0000520481.18933.f8

THE RESEARCHERS want to explore the notion that multiple genetic lesions within the group of genes might contribute to an accumulated risk for Parkinson's disease.

Researchers reported that patients with Parkinson's disease have a significant burden of variants among 54 genes known to be linked to lysosomal storage disorders, compared to controls. They said the finding represents new insight into the origins of the disease, which could shape future research and treatment.

BOSTON—Gene variants linked to lysosomal storage disorders predispose people to Parkinson's disease (PD), according to an analysis of a large, whole-exome sequencing dataset presented here at the AAN Annual Meeting in April.

Researchers found from whole exome sequencing data in over 2,900 subjects that patients with PD have a significant burden of variants among 54 genes known to be linked to lysosomal storage disorders, compared to controls. They said the finding represents new insight into the origins of the disease, which could shape future research and treatment. The link was also replicated using two independent cohorts.

“The gene set points to some very clear biology that could be targeted for further mechanistic investigation and therapy — the lysosome — which may be more important than any specific gene that is implicated here,” said Joshua Shulman, MD, PhD, assistant professor of neurology at Baylor College of Medicine in Houston, TX, who jointly led the study with Peter Heutink, PhD, a group leader at the German Center for Neurodegenerative Diseases in Tübingen, Germany.

Researchers suspect that dysfunctional lysosomes, which digest material that cells no longer need, play a role in PD. Glucocerebrosidase (GBA) and sphingomyelin phosphodiesterase 1 (SMPD1), both of which are lysosomal disorder storage disorder genes, have been found to be associated with a heightened risk of PD.

GBA causes Gaucher's disease, in which patients develop an enlarged liver and spleen; it usually does not have neurologic symptoms. SMPD1 predisposes people to Niemann-Pick's disease, which has wide-ranging effects, including cognitive and motor dysfunction.

“It was a bit of a surprise when previous researchers found that individuals who have Gaucher's disease are at a higher risk of Parkinson's disease,” said lead author Laurie Robak, MD, PhD, instructor of molecular and human genetics at Baylor, who presented the new findings at the AAN Annual Meeting. The predisposition for PD is for anyone with a GBA variant, whether or not they have Gaucher's, she noted.

“We propose an oligogenic model of PD, in which multiple genetic hits may act in combination to degrade lysosomal function, enhancing disease susceptibility.”

he innovation in this analysis, Dr. Shulman said, was to look more broadly. For that, they collaborated with the International Parkinson's Disease Genomics Consortium, which has obtained whole-exome sequencing for about 1,200 PD patients and about 1,500 controls. It's thought to be the largest whole-exome sequencing cohort in PD currently available.

DR. LAURIE ROBACK: “We propose an oligogenic model of PD, in which multiple genetic hits may act in combination to degrade lysosomal function, enhancing disease susceptibility.”

“The innovation here is looking at the genes as a group rather than trying to look singly at each specific gene,” Dr. Shulman said, although the group did also confirm the association of both GBA and SMPD1 with PD, and found links between PD and three other genes.

He said his group is “very excited” to pursue “the idea that one might accumulate risk for Parkinson's disease by having multiple genetic lesions within the group of genes. Because in our cohort, we find that half of Parkinson's cases had at least one genetic variant predicted to be damaging, and about 20 percent of the cohort has two or more variants.”

EXPERTS COMMENT

Andrew S. Feigin, MD, associate professor of neurology and molecular medicine at Hofstra Northwell School of Medicine in Hempstead, NY, said the findings offer new insights to the pathophysiology of Parkinson's disease.

Figure. DR. JOSHUA SHULMAN: “The innovation here is looking at the genes as a group rather than trying to look singly at each specific gene.”

“This is an important study because it confirms something that people have suspected for a while — namely that the association of Gaucher's disease with PD is not unique, but is representative of a more general association of lysosomal storage disorders with PD,” he said.

That said, Dr. Feigin added that he doesn't expect the findings to have a clinical impact right away, though it could in the future.

“I do not see any immediate clinical relevance of this study, nor do I think there is a specific/individual genetic abnormality that is key — at least not as far as we know,” he said. “The importance of the finding is more related to the possibility that this may lead to a better understanding of the underlying causes of PD, which could lead to novel therapeutic approaches.”

Caroline M. Tanner, MD, PhD, FAAN, professor of neurology at the University of California, San Francisco, whose research has focused on the etiology of Parkinson's disease, said that these new findings on the lysosomal storage pathway could be especially powerful when coupled with the consideration of environmental factors implicated in PD.

“A lot of the work that I do is look at environmental and genome interaction in terms of Parkinson's etiology,” she said. “There is less mechanistic work that has been done, but the amount that (has been done) suggests that those same pathways are affected by environmental exposure. So, it's probably, for most people, going to be finding a lot of these little individual susceptibilities. And then, what happens to you in life? Are you exposed to certain chemicals? What are your behaviors? Do you exercise a lot or not? How does that modify [that susceptibility]? And how does it interact with other things like mitochondrial function that gives a full picture?”

This combination of factors will likely be the best way to assess a lot of patients, she said. “For the majority of people who don't have clear dominant gene, that's the etiology pathogenesis of Parkinson's disease. And so, I think that fits perfectly with that kind of an idea.”

She added, “I also think that there's a big take-home message about certain things that people can do if they do find they have lower risk — like exercise. That can't hurt and definitely can help.”

“We're still a little bit at the threshold,” she said. “It's still hard to put it all together. I think the evidence for these pathways has been accumulating over a decade or so. It's actually very exciting.”

http://journals.lww.com/neurotodayonline/Fulltext/2017/05180/News_from_the_AAN_Annual_Meeting__Lysosomal.15.aspx

Parkinson-Related Dyskinesia May Respond to Dextromethorphan, Quinidine Combo

Shannon Aymes, MD May 18, 2017

Levodopa-induced dyskinesia can have an impact on quality of life in Parkinson disease.

A small, proof-of-concept study suggests dextromethorphan with quinidine may be a future treatment option for levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD). The results were published in Movement Disorders.1

Chronic levodopa therapy for PD may lead to LID. LID is associated with poorer quality of life and higher healthcare use. Potential therapeutic targets include serotonergic pathways, N-methyl-D-aspartate receptors (NMDA), and sigma-1 receptors. Of note, dextromethorphan is thought to have an impact on all three of these pathways, and combining dextromethorphan with quinidine increases the bioavailability of dextromethorphan by inhibiting CYP2D6.

Susan H. Fox, MB ChB, MRCP(UK), Ph, associate director of the movement disorders clinic at the University Health Network in Toronto, Canada, and colleagues sought to examine the efficacy and safety of dextromethorphan with quinidine for LID.  

The investigators conducted a proof-of-concept, randomized, placebo-controlled, double-blind, crossover study of patients with PD. The participants were randomly assigned to receive either dextromethorphan 45 mg plus quinidine 10 mg twice daily or placebo during 2 2-week crossover treatment periods. After a 2-week washout period, intravenous levodopa infusions over 2 hours were administered to the participants who were then monitored for dyskinesia severity.

In the 13 efficacy-evaluable participants, there was no significant difference in dyskinesia-severity for dextromethorphan with quinidine compared with placebo (area under the curve [AUC] 966.5 vs 1048.8, P =.191). However, in efficacy-evaluable participants who had 80% or more compliance with the study drug, the investigators reported lower dyskinesia-severity with post-hoc sensitivity analysis for infusion start time to 4 hours post-infusion (AUC 1585.0 vs 1911.3, P =.024). Further, 9 participants reported “much/very much improved” dyskinesia symptoms on the study drug.

Adverse events were reported in 11 out of the 13 participants (78.6%) while on the study drug. The most common adverse events were fatigue and somnolence and most were rated as mild to moderate.

“In conclusion, this proof-of-concept study provides preliminary evidence of a clinical benefit with DM 45 mg/Q 10 mg BID [twice a day] for treatment of LID in patients with PD,” the researchers wrote. The results will need to be confirmed in larger studies. 

Disclosures: The study was funded by a grant from the Michael J. Fox Foundation for Parkinson's Research given to Avanir Pharmaceuticals. Avanir Pharmaceuticals provided the clinical and medical monitoring, statistical analysis, and data management. Co-investigators SA Factor, LE Pope, N Knowles, and J Siffert report relationships with Avanir Pharmaceuticals.

Reference

Fox SH, Metman LV, Nutt JG, et al. Trial of dextromethorphan/quinidine to treat levodopa-induced dyskinesia in Parkinson's disease [published online March 30, 2017]. Mov Disord. doi:10.1002/mds.26976

http://www.neurologyadvisor.com/movement-disorders/parkinsons-dyskinesia-treatment-with-dextromethorphan-quinidine/article/662534/

Six non-motor symptoms of Parkinson’s that may surprise

May 18, 2017

(StatePoint) Those familiar with Parkinson’s disease (PD) are likely aware of the disorder’s most visible symptoms, including slower movements, impaired balance, rigidity/stiffness and involuntary shaking.

However, Parkinson’s, which is a neurodegenerative brain disorder, can cause a range of non-motor symptoms, which can bring about a new set of challenges for people with Parkinson’s and their caregivers.

It’s important to learn more about these non-motor symptoms, such as hallucinations, delusions and mood disorders, so the symptoms can be discussed with the doctor.

1. Hallucinations. More than half of all people with Parkinson’s will experience hallucinations or delusions over the course of their disease. Hallucinations can cause people to see, hear, or experience things that aren’t real.

For example, people with Parkinson’s commonly report seeing groups of people or animals that in actuality are not there. As hallucinations become more frequent, people with PD may become unable to distinguish what’s real and what’s imagined and react to their hallucinations.

Hallucinations can lead to increased patient and caregiver distress, and even nursing home placement.

2. Delusions. Delusions are false beliefs not supported by evidence, and in people with Parkinson’s, delusions often have paranoid themes. For example, a person with Parkinson’s might make accusations about their spouse or someone else trying to access their life savings. Another common delusion is even a longtime spouse committing adultery.

Studies have shown that many experiencing these symptoms are not reporting them to their doctors, possibly due to embarrassment or not understanding that the symptoms are associated with PD and the majority of the discussion is focused on motor symptoms.

3. Cognitive Changes. As explained by the National Parkinson Foundation, problems with attention, inability to focus on planning, difficulties with memory and language, and personality changes characterize the cognitive changes that can take place over time with PD.

4. Sleep Disorders. A range of sleep disorders are often associated with PD. They include insomnia, restless leg syndrome, talking or moving during sleep and excessive daytime sleepiness. Sleep disorders can impact overall health and well-being.

5. Mood Disorders. Depression, anxiety and irritability can also affect those with PD. In fact, one study showed that up to 40 percent of people with Parkinson’s will experience some form of anxiety during the course of their illness.

6. Additional Non-Motor Symptoms. The non-motor symptoms of PD are numerous, ranging from vision problems to hypertension to loss of sense of smell. These symptoms can also appear before a PD diagnosis and should be noted.

More information about Parkinson’s disease and its non-motor symptoms, such as hallucinations and delusions, can be found at www.parkinson.org.

While there is currently no cure for Parkinson’s disease, there are different treatment options, as well as assistive devices, to address motor and non-motor symptoms.

When people with Parkinson’s and their loved ones report the variety of symptoms that might be associated with the disease, it can help determine what treatment option is best for them.

http://www.sequoyahcountytimes.com/news/national_news/article_8df0a234-4c29-5a03-8eae-c5b3792a739f.html