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Friday, October 20, 2017

Tremor: Is it Essential Tremor or Tremor from Parkinson’s Disease?

By Editorial Team—October 20, 2017 



Tremor is one of the characteristic symptoms of Parkinson’s disease (PD), but it is also characteristic of essential tremor (ET), a neurological disorder that produces involuntary and rhythmic shaking. ET is approximately eight times more common than PD, and there are several other differences between the two conditions.1,2

Difference when the tremor occurs

In PD, the tremor is mostly seen at rest, when the body part is not being used, and may be referred to as “resting tremor.” In ET, the tremor occurs mostly during action or movement, such as when writing, eating, or holding a posture.2,3

Difference in frequency and magnitude of tremor

The tremor seen in ET is generally of a higher frequency (more repetitions over a length of time), although the frequency can decrease over time. In PD, the frequency of tremor is slower. The magnitude, or strength, of the tremor also differs: in PD the magnitude of tremor is high, whereas the tremor in ET can be variable throughout the day, ranging from very low to high magnitude.2,3

Difference in family history

In cases of PD, there is rarely a family history (estimated 10-20% of cases), but in ET, a family history of tremor is seen in more than 50% of cases.2,3

Difference in sides of the body affected

The tremor in PD usually starts on one side of the body and may develop on the other side as the disease progresses. In ET, the tremor usually affects both sides from the beginning of the condition.2

Differences in what improves tremor

People with PD who experience tremor usually experience improvement in their symptoms with levodopa therapy. People with ET may get relief from their tremor with primidone and propranolol. Also, the tremor from ET can be improved with alcohol consumption, whereas alcohol consumption has no effect on a tremor from PD.2

Differences in what parts of the body are affected

The hands are more often affected with tremor than the legs in people with PD, and the voice and head are almost never involved. In ET, the hands are also predominantly affected, but the tremor can also be present in the head and voice.2,3

Differences in other symptoms

In ET, tremor is the primary symptom. In PD, there are four primary symptoms, including tremor, rigiditybradykinesia (slowed movements), and balance issues.2,3

Differences in when it occurs

PD is most commonly diagnosed in people over the age of 60, although approximately 5-10% of people with PD are diagnosed younger than the age of 50. ET most often occurs during middle age, but it can occur at any age, even in childhood.3,4

Differences in handwriting

One of the symptoms of PD is micrographia, or very small handwriting. In ET, a person’s handwriting generally gets large and tremulous.3

Evaluation and diagnosis


Both ET and PD are movement disorders, and sometimes they can be mistaken for each other. However, there are many differences between the two conditions, and proper and early diagnosis is important for receiving the right treatment and support.
https://parkinsonsdisease.net/answers/differences-essential-tremor/

VIDEO: Directional deep brain stimulation: novel treatment options for all Parkinson’s patients

ADVANCES 


SPONSORED BY BOSTON SCIENTIFIC


Author: SPONSOREDPublished: 4 October 2017


Watch deep brain stimulation (DBS) experts Professor Pollo, Professor Timmermann, Professor Visser-Vanderwalle and Professor Volkmann explain the benefits of novel directional DBS systems for improved symptom control and fewer side effects

Every human brain is unique and every course of Parkinson’s disease has its own characteristics. In deep brain stimulation (DBS) therapy, physicians aim to target a very specific part of the brain – the subthalamic nucleus – in order to mitigate Parkinson’s symptoms.
Up until now, conventional DBS systems only allowed for stimulation with ring electrodes. With these electrodes, stimulation took the form of a ring around the electrode in the lead that was implanted into the patient’s brain. This meant that while physicians tried to target a very specific area of the brain, they always ran the risk of stimulating its neighbouring regions – since they could not steer the stimulation precisely. Unintended and unwanted stimulation could cause side effects such as speech problems.
The latest generation of DBS devices allow physicians to precisely steer the stimulation to target one specific area of the brain – significantly reducing side effects from unwanted stimulation. Our directional DBS systems use novel lead designs with segmented electrodes that allow the activation of individual electrode contacts. In addition, the technology in the pulse generator that powers the leads – the Multiple Independent Current Control (MICC) technology – allows the physician to specify exactly the amount of current needed for every contact of the electrode.
Through activating specific electrode contacts, and defining the amount of stimulation for each contact, stimulation precision is significantly increased. It is similar to shining a light on a specific spot with a flashlight. With the new systems, physicians now have full control of the stimulation steering and an increased set of stimulation options.
About deep brain stimulation (DBS) therapy
DBS uses a stimulator that is implanted into the patient’s chest. The stimulator sends mild electrical impulses to specific areas of the brain via thin wires called leads. This stimulation may help improve day-to-day experiences for people living with movement disorders such as Parkinson’s disease, dystonia, or essential tremor.

This article is sponsored by Boston Scientific. The information in this article is given for information purposes only and does not represent an endorsement by the EPDA of any particular treatments, products or companies. This article is not a substitute for advice from your doctor, pharmacist or other healthcare professional. Parkinson’s Life makes no representations or warranties of any kind, express or implied, about the completeness or accuracy of information provided.

http://parkinsonslife.eu/video-directional-deep-brain-stimulation-novel-treatment-options-for-all-parkinsons-patients/

TIPS FOR GOOD COMMUNICATION


Like all relationships, partnerships between Parkinson’s patients and their loved ones depend on good communication and mutual trust. Here are some ways to help strengthen communication:
  • Set expectations. Family and friends can sometimes feel helpless or feel they can only do so much. Let them know that listening, and offering empathy and support, is often all you need. 
  • Be clear. Discuss your needs openly. Whether it’s about your emotions or your symptoms, being as clear and direct as possible can help.
  • Listen. Listening to others can be just as important. Your family and friends may be able to observe things you can’t and share them with you and your doctor.
  • Be respectful of their experience. You’re living with Parkinson’s, and so are your family and friends. Recognize that their lives have also changed and that they may need time to adjust.
  • Make your relationship about more than the disease. You are each more than Parkinson’s, and you had a life “before Parkinson’s.” Keep in touch with the love and mutual interests that sustained your relationship before the disease.
  • Learn to ask for help from family and friends. Many people want to help, but don’t know what to offer. They may be waiting for you to ask. So be specific about what you need from those around you and you may find they are happy to help and respond readily to your request. 
  • Use humor. Sound silly? Maybe, but humor helps people feel better about themselves and the situation they’re in. It can help make a tough conversation easier. 

https://www.partnersinparkinsons.org/communication-tips

In the Pipeline-Parkinson's Disease: Why a Common Asthma Drug Could Be a Disease Modifier for Parkinson's Disease

 Robinson, Richard  Neurology Today: October 19, 2017
Volume 17 - Issue 20 - p 1,23–23 doi: 10.1097/01.NT.0000526677.81786.42


Researchers reported evidence suggesting that treatment with an asthma drug was associated with a steep decline in risk for development of Parkinson's disease in a population-wide prescription database from Norway. They offered molecular evidence that beta2-adrenoreceptors are linked to transcription of alpha-synuclein, and may therefore be a potential target for therapies.
The common asthma drug salbutamol (also called albuterol) reduces expression of alpha-synuclein, the protein at the core of Lewy bodies in Parkinson's disease (PD), and improves neuronal survival in several preclinical models. What's more, and potentially more important for the human disease, treatment with salbutamol was associated with a steep decline in risk for development of PD in a population-wide prescription database from Norway.
“These findings are exciting and potentially have important implications for neuroprotection in Parkinson's disease,” said Anthony E. Lang, MD, FAAN, professor of neurology and director of the Program in Parkinson's Disease at the University of Toronto, who was not involved in the study, which was published in the September 1 issue of Science.
Clearance of misfolded alpha-synuclein has been the focus of much work in PD, but until this paper, no group has reported a search for compounds that would reduce its production.
“We hypothesized that this would be the most direct solution,” said principal investigator Clemens R. Scherzer, MD, associate professor of neurology at Harvard Medical School and Brigham & Women's Hospital in Boston.
That such down-regulation might be possible was suggested by previous discoveries by Dr. Scherzer's group, when they identified multiple transcription factors that directly control the gene. “This suggested a gene-regulatory path for lowering alpha-synuclein and inspired our gene expression drug screen in the current work,” he said.

STUDY DESIGN

To conduct that screen, the researchers exposed neuroblastoma cells to more than one thousand compounds, including natural products and Food and Drug Administration (FDA)-approved drugs, looking for those that reduced production of alpha-synuclein. After a multi-stage replication process, four compounds emerged, three of which — salbutamol, clenbuterol, and metaproterenol — are beta2-adrenoreceptor agonists. All three are prescribed for asthma. Salbutamol and metaproterenol are approved by the FDA, while clenbuterol is not, but it is prescribed in Europe. Intriguingly, the fourth compound was riluzole, approved for treatment of amyotrophic lateral sclerosis.
Each of the three beta2-adrenoreceptor agonists reduced alpha-synuclein protein expression in a dose-dependent manner to about 75 percent of normal in the cell-based screen. In mice, 24 hours of treatment with clenbuterol lowered alpha-synuclein production in the substantia nigra. And in patient cells from individuals with an alpha-synuclein triplication, clenbuterol treatment also reduced protein production.
The team found molecular evidence suggesting that treatment with clenbuterol decreased histone acetylation at sites regulating transcription of the alpha-synuclein gene, a change that would be likely to reduce transcription factor access to the gene, which may account for the reduced production of the protein.
Further supporting a direct role for the beta2-adrenoreceptor in regulating alpha-synuclein production, the team found that knocking out the gene for the receptor, and thus preventing it from signaling at all, more than doubled alpha-synuclein levels in neurons.
“Thus, beta2-adrenoreceptors are linked to transcription of alpha-synuclein,” Dr. Scherzer said, and may therefore be a potential target for therapies.
To test that hypothesis in humans, he and his team turned to the Norwegian Prescription Database, which contains complete information on prescriptions for the 4.6 million residents of the country, beginning in 2004. Over six years of follow-up, the proportion of people not developing PD was highest among those who had received salbutamol for at least 180 days during follow-up (n=69,511), was intermediate among those who had received it for between 60 and 180 days (72,911), and was lowest among those receiving it for less than 60 days, or never. Taking all salbutamol users together, the rate ratio was 0.66, with a 95% confidence interval of 0.58 to 0.76.
One possible link between asthma treatment and reduced PD risk might be smoking, Dr. Scherzer said, which is a behavior known to both increase asthma and reduce the likelihood of developing PD. But if the observed risk reduction were explained by a link through smoking, one would expect other asthma drugs, such as inhaled corticosteroids, which don't act through the beta2-adrenergic receptor, to also be associated with reduced PD risk. This was not the case, he said, “so it is unlikely smoking can fully account for this association.”
Based on these findings, Dr. Scherzer said it was logical to begin thinking about a clinical trial of a beta2-adrenergic receptor agonist to determine if it can slow development of PD after diagnosis. However, he cautioned, “there is reason to rethink the paradigm of how clinical trials are traditionally designed and conducted for PD,” noting the consistent failure of treatments intended for disease modification in recent decades.
Dr. Scherzer turned up another surprising result in the population study, strengthening the conclusion that beta2-adrenergic receptor signaling influences development of PD. He found that exposure to propranolol, which blocks this receptor, markedly increased PD risk, with a rate ratio of 2.2 (95% CI 1.62 to 3.00). Back in the lab, his team showed that propranolol increased histone acetylation near the alpha-synuclein gene, increased protein production, and abrogated clenbuterol's ability to lower alpha-synuclein levels.
“Our data raise the concern that propranolol might increase the risk of Parkinson's disease, and that is worrisome,” Dr. Scherzer said. “At the same time, it's too early to draw firm conclusions for clinical practice. More research and replication in other populations is warranted to clarify this question.”




EXPERT COMMENTARY

“This is a pretty well-investigated area, so the discovery of a receptor of this type that regulates alpha-synuclein is surprising,” said Steven Finkbeiner, MD, PhD, director of the Taube/Koret Center for Neurodegenerative Disease and Gladstone Institutes and professor in the departments of neurology and physiology at the University of California, San Francisco, who was not involved with the study.
“Although the effect in cell models is modest, it is possible that this might be sufficient to produce a meaningful effect on Parkinson's risk, based on what we know about the effects of gene duplication and triplication and non-coding variants,” Dr. Finkbeiner said. “And the rate ratio reduction to 0.66 in the treatment cohort compared to the untreated one is potentially quite remarkable.”
But there are important unanswered questions, Dr. Finkbeiner added. The proposed mechanism, through modification of histone acetylation, “suggests that the drug is probably regulating many genes. Is modest reduction in alpha-synuclein responsible for the effects or are other targets even more important?”
Dr. Lang of Toronto added: “The concept of screening compounds that reduce transcription of the alpha-synuclein gene is novel, and the preclinical science looks very strong. The finding that propranolol has an opposite effect is very interesting and complies with the hypothesis very nicely.”
But the real importance of the paper comes from the epidemiologic data, Dr. Lang said. “We have failed to develop effective treatments with our toxin models of PD, and now we have models that over-express alpha-synuclein, and there are likely to be a lot of failures from these as well.” The difference here is that the benefits seen in the preclinical work seem to also be operating in a large human population, he said, adding: “But that needs to be confirmed in other databases.”
The Norwegian data raise several important questions that will need to be addressed as well, he said. “The effect of salbutamol appears to be rapid and quite profound. If that's the case, why haven't we seen this in epidemiological studies before?”
Regarding the propranolol effect on PD risk, he noted that propranolol is also used in PD to treat postural and action tremor. “But we never see the other features of the disease get worse,” which might be expected if the drug can increase alpha-synuclein production strongly enough to dramatically increase PD risk. “Why aren't we seeing propranolol worsening pre-existing Parkinson's disease?”
“I think the basic science here is really compelling, and it moves us in a completely new direction,” Dr. Lang said. “But the epidemiology is really where most people will look before taking this into clinical trials. That would be one of the more important things to reproduce as quickly as possible.”
http://journals.lww.com/neurotodayonline/Fulltext/2017/10190/In_the_Pipeline_Parkinson_s_Disease__Why_a_Common.1.aspx

Parkinson’s Disease: Do You Know These Early Warning Signs?

October 20, 2017

Symptoms can occur long before tremors



Just one correction:  dopamine (not levodopa) is the natural chemical found in the brain that is lacking or not being produced in enough quantities in a Parkinson’s. Levodopa (the pill) gets converted to dopamine when it reaches the brain.
Most people recognize the later stages of Parkinson’s disease — tremors and a shuffling walk are the most common signs. But the condition is difficult to diagnose early on; doctors don’t pinpoint most cases until they’re well past the initial stages. So is there a way to spot signs and seek treatment earlier?
Yes, but you need to know what to look for.
The vague symptoms of Parkinson’s could point to many problems. That’s what makes early specific diagnosis difficult. And that’s what frustrates those who search for reasons behind your movement problems.
But, there are recognizable signs that could at least put you and your doctor on alert, says neurologist Hubert Fernandez, MD, Director of Cleveland Clinic’s Center for Neurological Restoration. And getting a neurologist involved earlier is the key, he says.
“It’s not uncommon for patients to see a rheumatologist or orthopedist for six months to a year for pain in the right shoulder or dragging the right leg. They might even get steroid injections that don’t work,” he says. “But, only a neurologist can diagnose Parkinson’s.”

Symptoms follow stages of the disease

Parkinson’s motor problems are quickly recognizable, Dr. Fernandez says. The tremors — rhythmic movement of lips, chin, hands and legs; rigidity; stiffness and slowness are hallmark signs. Balance and gait problems are also common.
But, Parkinson’s symptoms start long before these problems emerge. As a progressive disease, Parkinson’s destroys the brain’s nerves from the bottom up, he says.
Stage 1: Parkinson’s attacks the base of the brain stem — the medulla — initially. This may cause constipation and can cause people to lose their sense of smell. These symptoms could strike decades before you see your first tell-tale tremor, Dr. Fernandez says.
Stage 2: Nerve deterioration in the pons (the brain’s message center) is next. Damage at this stage may lead to depression and REM sleep disorder. A person may “act out” their dreams while they sleep, potentially hurting themselves or others.
Stage 3: The tremor and shuffle appear here because the disease is attacking the part of the brain largely responsible for movement.
Stage 4 and 5: These are the most advanced Parkinson’s stages. Dementia and hallucinations often occur at this point.

When should you consult a neurologist?

Of course, not everyone who experiences constipation or depression, or who loses the sense of smell is at risk for developing Parkinson’s disease, Dr. Fernandez says. But, if you have those problems along with any of these factors, make an appointment with a neurologist:
  • First-degree relative with Parkinson’s with onset before age 60
  • One of the four motor features: resting tremor, stiffness, slowness, gait/balance problems
  • Repeated head trauma
  • REM sleep disorder

4 things you should know about Parkinson’s

In addition to learning what symptoms to watch for, there are four things you should know, Dr. Fernandez says:
1. It’s a progressive disease. Parkinson’s disease worsens over time, but each patient progresses differently. Doctors will treat the symptoms to limit how much they impact your daily life.
2. The cause is largely unknown. In 95 percent of cases, doctors don’t know why patients develop Parkinson’s. Often, a combination of factors are involved, including genetic susceptibility and environmental factors (such as having multiple head injuries). Research shows that genetic mutations are responsible for the rest of cases.
“We don’t know what factors contribute to Parkinson’s,” he says. “And, we’re just beginning to uncover the susceptibility genes.”
3. Treatment is symptom-dependent. How bothersome your symptoms are will determine how aggressively your doctor treats your disease. If your symptoms don’t disrupt your daily functioning, he or she likely will postpone prescribing medication.
Dopamine, a chemical found naturally in the brain, is lacking or not produced in high enough quantities in people with Parkinson’s disease. Patients may take levodopa, a pill that is converted to dopamine when it reaches the brain. This helps manage Parkinson’s symptoms.
It is often prescribed with a second drug called carbidopa, which prevents the nausea that can be caused by levodopa alone.
Doctors also may use deep brain stimulation to treat you if you don’t get relief with levodopa, Dr. Fernandez says.
4. Stroke, infection or other neurological conditions can mimic Parkinson’s. Don’t make any assumptions about your condition before you see a neurologist or Parkinson’s expert for a proper diagnosis.
Ultimately, remember that your journey with Parkinson’s is unique — so work closely with your doctor, Dr. Fernandez says.
“It’s important to remember that everyone’s experience with Parkinson’s is different, and treating it is about targeting the symptoms,” he says. “The most important thing is getting a good evaluation by a neurologist or Parkinson’s expert to make sure you’re on the right path.”

 / 
https://health.clevelandclinic.org/2017/10/are-you-at-risk-for-parkinsons-disease-4-things-to-know/

Deep Sleep Linked to Cognitive Performance in Parkinson's

Nancy A. Melville
October 20, 2017



SAN DIEGO — Patients with Parkinson's disease who have higher levels of slow-wave, or deep, sleep show significantly higher performance on a variety cognitive measures compared with those who have lower slow-wave sleep levels, despite no differences between the groups' subjective measures of daytime sleepiness.
"We found that sleep has a significant influence on cognitive performance in Parkinson's disease," said first author, Amy W. Amara, MD, from the University of Alabama, Birmingham, in presenting the findings here at the ANA 2017: 48th Annual Meeting of the American Neurological Association.
"These findings suggest that interventions to improve sleep might improve cognitive function as well."
Sleep dysfunction is common in Parkinson's disease, resulting from multifactorial causes ranging from nocturnal motor symptoms of the disease to side effects from various drugs.
To take a closer look at the quality of sleep — specifically the role of deep, or slow-wave, sleep, defined as non–rapid eye movement (REM) stage 3 sleep — in cognitive measures in Parkinson's disease, Dr Amara and her colleagues enrolled 32 patients with Parkinson's disease. They underwent polysomnography and subsequently were evaluated for sleepiness and psychomotor skills.
The patients were categorized as having high slow-wave sleep, defined as more than 10% of the time in non-REM stage 3, or having low slow-wave sleep, defined as 10% or less time in non-REM stage 3 sleep.
Age, education, and disease severity did not differ between the two groups, but there were more women in the high slow-wave sleep than the low slow-wave sleep group.
Despite the differences in time spent in deep sleep, no differences were seen between the two groups' subjective measures of daytime sleepiness, assessed on the Epworth Sleepiness Scale, or in their reports of sleep quality, assessed on the Pittsburgh Sleep Quality Index.
There were, however, important differences in neurocognitive measures: Patients with high slow-wave sleep showed significantly faster reciprocal reaction time on the Psychomotor Vigilance Task (P = .04), and they performed significantly better on measures of global cognition, including the Montreal Cognitive Assessment (P = .04), attention/working memory (Stroop color naming: P = .0006; word naming: P = .0025; letter number sequencing: P = .031).
In addition, patients with higher slow-wave sleep had higher scores in executive function (Trails B-A: P = .01; Stroop inhibition: P = .0052), as well as one of the two measures of language (Controlled Oral Word Association: = .021).
Findings on memory and visuospatial function assessments did not significantly differ between groups, and none of the results changed after controlling for sex.
In an opinion statement published in July in Current Treatment Options in Neurology, Dr Amara and her colleagues further discussed sleep disruption in Parkinson's disease and the potential treatments.
"While the optimal treatment for insomnia in Parkinson's disease has not been established, available strategies include cognitive-behavioral therapy, medications with soporific properties, and light therapy," they wrote.
Safety measures, clonazepam, and melatonin are the mainstays of treatment for REM sleep behavior disorder, while continuous positive-airway pressure is an effective treatment for sleep-disordered breathing in Parkinson's disease, they said.
Another notable sleep disturbance in Parkinson's disease is circadian rhythm disturbance.
Circadian disruption has emerged as an important etiology of impaired sleep-wake cycles in Parkinson's disease, and circadian-based interventions hold promise for novel treatment approaches," they said.
The new study adds to the understanding of how Parkinson's disease is affected by such sleep disturbances, commented Kathleen Poston, MD, associate professor of neurology and neurological sciences and neurosurgery at Stanford University Medical Center, in California, who co-moderated the session.
"Insomnia is a common nonmotor symptom in Parkinson's disease, which patients often discuss with their physicians," she told Medscape Medical News.
"This study adds to our understanding of insomnia in Parkinson's by identifying a specific part of sleep, known as slow-wave-sleep, that seems to be specifically impacted in patients with Parkinson's disease."
Dr Poston noted that a wide range of factors can have cognitive effects in Parkinson's disease, and the study doesn't necessarily imply causation of poor slow-wave sleep on low cognitive scores. However, it raises important issues for further study.
"Cognitive performance is extremely multifactorial, and researchers have just begun to understand all of the different genetic, biological, and clinical factors that impact low cognitive performance," Dr Poston said.
"Sleep is often implicated as one of those potential causes, and this study supports that idea. Further, it supports the idea that the connection between sleep and cognition is important to study in the future."
The authors and Dr Poston have disclosed no relevant financial relationships.
ANA 2017: 48th Annual Meeting of the American Neurological Association. Abstract S272. Presented October 15, 2017.
https://www.medscape.com/viewarticle/887405#vp_1

Key Psychiatric Drug Target Comes Into Focus

Oct 20, 2017 | Original Story by Nicholas Weiler for the University of California San Francisco.


Researchers have determined the crystal structure of a specific dopamine receptor called D4 at an incredibly high resolution. Credit: University of California San Francisco.


One way or another, many psychiatric drugs work by binding to receptor molecules in the brain that are sensitive to the neurotransmitter dopamine, a chemical signal that is central to how our experiences shape our behavior. But because scientists still don’t understand the differences between the many kinds of dopamine receptors present on brain cells, most of these drugs are “messy,” binding to multiple different dopamine receptor molecules and leading to serious side effects ranging from movement disorders to pathological gambling.

Now, researchers at UC San Francisco, the University of North Carolina-Chapel Hill, and Stanford University report a major step forward toward designing more powerful psychiatric drugs with fewer side effects.


As reported online on Oct. 19, 2017, in Science, the team has determined (“solved” in the terminology of structural biology) the crystal structure of a specific dopamine receptor called D4 at an incredibly high resolution – the highest for any dopamine, serotonin, or epinephrine (aka adrenaline) receptor to date – allowing them to design a new compound that tightly binds only to D4 and none of the other 320 receptors they tested.


Earlier this year, the same team solved the crystal structure of LSD bound to a serotonin receptor to learn why acid trips last so long and how to perhaps tweak the drug to be less potent.


The D4 dopamine receptor has been implicated in attention deficit/hyperactivity disorder (ADHD), cancer metastasis, and even erectile dysfunction. Similar dopamine receptor subtypes are crucial factors in conditions including schizophrenia, addiction, Alzheimer’s disease, depression, and Parkinson’s disease. However, there are currently few specific drugs for the D4 subtype that can target it and it alone, which has prevented researchers from isolating the specific function of D4 compared to other dopamine receptors. Current drugs that target dopamine receptors also cause side effects such as Parkinson’s-like movement disorders.


“We now have the ability to get a crystal-clear image of these receptors to see details like never before,” said co-senior author Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics at the UNC School of Medicine. “That’s the key. Seeing these details allowed us to create a compound that tightly binds only to one kind of receptor. Our ultimate goal is to avoid so-called ‘scattershot drugs’ that hit many unwanted receptors and cause serious and potentially fatal side effects.”


Brian Shoichet, PhD, co-senior author and professor of pharmaceutical chemistry in UCSF’s School of Pharmacy, said, “Our computational modeling capabilities allowed us to virtually screen over 600,000 compounds much faster than traditional screening methods and create a hierarchy of compounds that potentially bind only to the D4 dopamine receptor. Our work to create better drugs is far from over, but the computer-based screening tools used here are becoming an ever-more reliable tool in our arsenal.”


Collaborators Crack the Case Using Crystals, Computers


Dopamine receptors are part of a large family of molecules called G protein-coupled receptors, or GPCRs, which are the intended targets of approximately 35 percent of all drugs on the market. Despite their importance, very little is known about the structures of the vast majority of GPCRs, including D4 and other dopamine receptors, making it challenging to design more precise drugs with fewer side effects.


Typically, scientists have solved the chemical structure of proteins using a technique called X-ray crystallography: they cause the protein to condense into a tightly packed crystal lattice, then shoot x-rays at the crystal and can calculate the protein’s structure from the resulting diffraction patterns. However, getting the D4 protein to crystallize with a drug bound to it — in order to pinpoint the receptor’s site of action — had proved an unsolved challenge.


To solve the high-resolution structure of D4, Roth lab postdocs Sheng Wang, PhD, and Daniel Wacker, PhD, – two of three co-first authors – conducted a series of intense experiments over three years to get the D4 receptor to crystallize. They dissolved receptor molecules in water-based buffers and then slowly removed the water. Then, in order to be sure the receptors were sitting perfectly still so they could be imaged, Wang and Wacker employed a variety of experimental tricks – outlined in the Science paper – to carefully draw out water at the exact right conditions until the receptors were packed tightly into crystals that could then be bombarded with X-rays. The result was the first-ever super high-resolution image of the chemical architecture of D4 bound to the antipsychotic drug nemonapride.


“We had to get a high-resolution structure like this so we could see exactly how a compound can bind to D4,” Wang said. “It’s like seeing details in a photograph that you just couldn’t see unless the photo was super high resolution. Once we had that, we teamed up with our UCSF colleagues to computationally screen for compounds that might potentially bind to this receptor but not others.”


Anat Levit, PhD, a postdoc in Shoichet’s lab at UCSF and the third co-first author, led the computational modeling and new compound discovery, in collaboration with co-author Ron Dror, PhD, and his Stanford lab.


“Theoretically, there’s an almost infinite number of chemical compounds that could be made, and this chemical space is enormous and largely unexplored. However, we have large libraries of virtual compounds that at least edge into this space,” Levit said. “Using the new high-resolution structure and our computational modeling program, we fit each of 600,000 virtual compounds into the dopamine/nemonapride binding site of the D4 receptor, as you might fit candidate puzzle pieces into a partially constructed puzzle.” 


Levit and colleagues in the Shoichet lab evaluated all 600,000 of these chemical “puzzle pieces” to see how well they fit into the full D4 receptor that the Roth lab team had solved. Once they had identified the top ten candidate compounds that computer modeling pointed to as likely binding partners with the D4 receptor, they sent them back to Wang and Wacker to test experimentally in the lab.


The Roth lab team found that two of the compounds indeed fit into the D4 receptor, but did so relatively loosely.


“The initial two compounds were just starting points,” Wacker said. “A drug or even a ‘probe’ used to explore the biology of the receptor must fit the receptor tightly. A compound needs to stay attached for a period of time to have an effect inside the cell.”


The research then bounced back and forth between the computer modelers at UCSF and the experimental lab at UNC-Chapel Hill to design and test dozens of new chemical compounds that might bind tighter to the D4 receptor.


Finally, by tinkering with chemical links and ionic attractions here, adding new chemical groups there, Levit identified a virtual compound — compound UCSF924 — that computer simulations suggested could bind extremely tightly to the D4 receptor. Upon testing this compound in the lab, Wang confirmed the molecule could bind to the D4 receptor 1000-times more powerfully than the initial virtual compounds.


Helping Researchers Understand Specific Receptors


The researchers now plan to test their new compound in animal models to determine exactly how it activates the D4 receptor, and how activating the D4 receptor alone alters brain function.


“No one knows what the D4 receptor precisely does,” Wang said. “The high specificity and high potency of this new compound will allow us to begin to address this for the first time.”


The team also plans to use the highly-selective UCSF924 compound to learn more details of how existing drugs work by altering specific cellular pathways inside cells.


“This work has implications beyond D4,” Wacker said. “For instance, antipsychotics are dirty drugs; they hit everything. To better understand them and improve upon them, we need to understand what they do at every single target they hit. Our work is an important step toward that goal.” 


Shoichet added, “Whereas UCSF924 is far from a drug, it is a great probe, and we are making it openly available to the community via Sigma-Aldrich, as SML2022.” 


Looking back on progress in this field, Shoichet said, “When structure- and computer-based screens were first developed at UCSF 30 years ago, the idea that we would have such beautiful views of drug targets as crucial and subtle as the dopamine D4 receptor, and that we could exploit it so quickly and effectively, was far from anyone’s mind. But the National Institutes of Health invested in these lines of basic research for decades. Now that long-term research effort is beginning to pay off in the ability to computationally screen new GPCR targets and find new and exciting chemical leads for biology and for drug discovery.”

This article has been republished from materials provided by University of California San Francisco. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference
Sheng Wang, Daniel Wacker, Anat Levit, Tao Che, Robin M. Betz, John D. McCorvy, A. J. Venkatakrishnan, Xi-Ping Huang, Ron O. Dror, Brian K. Shoichet, Bryan L. Roth. D4dopamine receptor high-resolution structures enable the discovery of selective agonists. Science, 2017; 358 (6361): 381 DOI: 10.1126/science.aan5468

https://www.technologynetworks.com/tn/news/key-psychiatric-drug-target-comes-into-focus-293425

Thursday, October 19, 2017

Binding Sites on Amyloid Beta Peptide Discovered

NEUROSCIENCE NEWS    OCTOBER 19, 2017

Summary: Researchers have invented a probe that lights up when it binds to a misfolded amyloid peptide.


Source: Rice University.

A rhenium-based complex developed at Rice University binds to fibrils of misfolded amyloid beta peptide, which marks the location of a hydrophobic cleft that could serve as a drug target, and oxidizes the fibril, which changes its chemistry in a way that could prevent further aggregation. NeuroscienceNews.com image is credited to Martí Group/Rice University.


A probe invented at Rice University that lights up when it binds to a misfolded amyloid beta peptide — the kind suspected of causing Alzheimer’s disease — has identified a specific binding site on the protein that could facilitate better drugs to treat the disease.

Even better, the lab has discovered that when the metallic probe is illuminated, it catalyzes oxidation of the protein in a way they believe might keep it from aggregating in the brains of patients.

The study done on long amyloid fibrils backs up computer simulations by colleagues at the University of Miami that predicted the photoluminescent metal complex would attach itself to the amyloid peptide near a hydrophobic (water-avoiding) cleft that appears on the surface of the fibril aggregate. That cleft presents a new target for drugs.

Finding the site was relatively simple once the lab of Rice chemist Angel Martí used its rhenium-based complexes to target fibrils. The light-switching complex glows when hit with ultraviolet light, but when it binds to the fibril it becomes more than 100 times brighter and causes oxidation of the amyloid peptide.

“It’s like walking on the beach,” Marti said. “You can see that someone was there before you by looking at footprints in the sand. While we cannot see the rhenium complex, we can find the oxidation (footprint) it produces on the amyloid peptide.

“That oxidation only happens right next to the place where it binds,” he said. “The real importance of this research is that allows us to see with a high degree of certainty where molecules can interact with amyloid beta fibrils.”

The study appears in the journal Chem.

“We believe this hydrophobic cleft is a general binding site (on amyloid beta) for molecules,” Martí said. “This is important because amyloid beta aggregation has been associated with the onset of Alzheimer’s disease. We know that fibrillar insoluble amyloid beta is toxic to cell cultures. Soluble amyloid oligomers that are made of several misfolded units of amyloid beta are also toxic to cells, probably even more than fibrillar.

“There’s an interest in finding medications that will quench the deleterious effects of amyloid beta aggregates,” he said. “But to create drugs for these, we first need to know how drugs or molecules in general can bind and interact with these fibrils, and this was not well-known. Now we have a better idea of what the molecule needs to interact with these fibrils.”

When amyloid peptides fold properly, they hide their hydrophobic residues while exposing their hydrophilic (water-attracting) residues to water. That makes the proteins soluble, Martí said. But when amyloid beta misfolds, it leaves two hydrophobic residues, known as Valine 18 and Phenylalanine 20, exposed to create the hydrophobic cleft.

“It’s perfect, because then molecules with hydrophobic domains are driven to bind there,” Martí said. “They are compatible with this hydrophobic cleft and associate with the fibril, forming a strong interaction.”

If the resulting oxidation keeps the fibrils from aggregating farther into the sticky substance found in the brains of Alzheimer’s patients, it may be the start of a useful strategy to stop aggregation before symptoms of the disease appear.

“It’s a very attractive system because it uses light, which is a cheap resource,” Martí said. “If we can modify complexes so they absorb red light, which is transparent to tissue, we might be able to perform these photochemical modifications in living animals, and maybe someday in humans.”

He said light activation allows the researchers to have “exquisite control” of oxidation.
“We imagine it might be possible someday to prevent symptoms of Alzheimer’s by targeting amyloid beta in the same way we treat cholesterol in people now to prevent cardiovascular disease,” Martí said. “That would be wonderful.”
ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

The Welch Foundation and National Science Foundation supported the research. The Center of Computational Science at the University of Miami provided computational resources.

Source: David Ruth – Rice University
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Martí Group/Rice University.
Original Research: Abstract for “Photochemical Identification of Molecular Binding Sites on the Surface of Amyloid-β Fibrillar Aggregates” by Amir Aliyan, Thomas J. Paul, Bo Jiang, Christopher Pennington, Gaurav Sharma, Rajeev Prabhakar, and Angel A. Martí in Chem. Published online October 19 2017 doi:10.1016/j.chempr.2017.09.011


Abstract

Photochemical Identification of Molecular Binding Sites on the Surface of Amyloid-β Fibrillar Aggregates

Highlights
•A rhenium dipyridophenazine carbonyl complex binds to Aβ fibrils
•Molecular dynamics simulations predict that binding occurs at the Phe20-Val18 cleft
•Photoirradiation of the complex causes oxidation on the Aβ fibril
•MS-MS experiments show oxidation at Met 35, consistent with Phe20-Val18 binding

The Bigger Picture
Alzheimer’s disease is a form of dementia affecting over 44 million people worldwide, and its symptoms include agitation, confusion, and memory loss. This disease is characterized by aggregates of the amyloid-β (Aβ) peptide in the brain. The transition of Aβ from the soluble to the aggregated form is linked to the onset of Alzheimer’s disease. Molecules that inhibit Aβ aggregation or quench its harmful effect are highly sought after. However, how molecules bind to Aβ is still uncertain. Aβ aggregates are disordered in nature, preventing the use of common methods for studying structure and binding. To address this, we used a rhenium complex that binds to Aβ. Upon light exposure, this complex produces oxidation on Aβ, leaving a mark at the place of binding. Spectroscopic and computational studies allowed elucidation of locations and binding modes of these molecules on Aβ. This information will guide the production of potent drugs with better binding affinities to Aβ for the treatment of Alzheimer’s disease.

Summary
The aggregation of amyloid-β (Aβ) into insoluble fibrils has been associated with the development of Alzheimer’s disease. The study of Aβ aggregation with [Re(CO)3(dppz)(Py)]+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine; Py = pyridine) has led to the observation of an irradiation-induced light-switching response accompanied by the oxidation of the Aβ fibril. Here, we used the photophysical and photochemical properties of this complex, as well as spectroscopic and computational methods, to elucidate molecular binding sites on Aβ fibrils. [Re(CO)3(dppz)(Py)]+ binds to Aβ fibrils with a dissociation constant of 4.2 μM and a binding stoichiometry 2.8:1 (Aβ/complex). Molecular dynamics (MD) simulations predicted binding of [Re(CO)3(dppz)(Py)]+ through a hydrophobic cleft on the fibril axis between Val18 and Phe20. Tandem mass spectrometry analysis indicated that oxidation occurred at Met35, footprinting the place of binding, which is close to the site predicted by the MD simulations. Finding binding sites in Aβ is of great importance for the design of Aβ-binding drugs.

“Photochemical Identification of Molecular Binding Sites on the Surface of Amyloid-β Fibrillar Aggregates” by Amir Aliyan, Thomas J. Paul, Bo Jiang, Christopher Pennington, Gaurav Sharma, Rajeev Prabhakar, and Angel A. Martí in Chem. Published online October 19 2017 doi:10.1016/j.chempr.2017.09.011

http://neurosciencenews.com/amyloid-beta-peptide-binding-7773/