Are You Wearing Spandex or a Potato Sack?

NOVEMBER 4, 2019 BY  "SHERRI WOODBRIDGE"

“You don’t look like you have Parkinson’s disease.” It’s a common refrain heard by those in our community. Everyone’s perception of this disease is different. And everyone wears Parkinson’s differently.

Recently, a graphic circulated among the Parkinson’s disease (PD) community showing the visible and invisible symptoms associated with the disease. Those who don’t look like they have Parkinson’s likely struggle more with invisible symptoms.

Outward symptoms of Parkinson’s disease

Visible signs of PD include rigidity of the muscles, dystonia, and tremors. These can be seen in the extremities, as well as the jaw, lips, and other parts of the body. Akinesia, bradykinesia, balancing issues, and even handwriting fit this category.

Visible signs stick out like a sore thumb. It’s like wearing a tight, ill-fitting, neon orange, one-piece spandex exercise outfit. Every curve is accentuated in an unattractive way.

Every bulge sticks out, drawing stares and whispers.

Internal symptoms of Parkinson’s disease

Hidden symptoms make diagnosing PD more difficult; minimal visible symptoms can mimic other diseases.

It’s like wearing a potato sack: You can’t tell what is underneath. But invisible symptoms are often greater in number than those that can be seen.

Insomnia and others sleep issues are common. Depression, panic attacks, apathy, hallucinations, dementia, and anxiety are often taboo subjects that need to be addressed. Patients struggle with swallowing difficulties, aspirating, speech problems, and gastric reflux. They don’t talk about the bladder and erectile dysfunction — or the constipation.

What’s wrong with your face?

A lack of facial expression (known as masking, or stone face, among the PD community) may come into play. And a loss of smell may come as a surprise, but it can have its benefits.

Pain should never be ignored as a potential symptom of Parkinson’s disease. While it may not be associated with your individual PD outfit, it is part of the potato-sack cover-up.

Whether an outfit is made of spandex or a potato sack, the symptoms are real. They can be devastating and overwhelming.

We need to remember that no matter what our symptoms look like, we are not alone. We are on this journey together.

***

Note: 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. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.

https://parkinsonsnewstoday.com/2019/11/04/spandex-invisible-symptoms/

Algorithm for Wearable Sensors Ably Measures Tremor Severity as Patients Go About Daily Life, Study Says

 NOVEMBER 4, 2019 BY CATARINA SILVA, MSC

Researchers have developed algorithms that work with wearable sensors to continuously monitor tremor, and estimate total tremor, in Parkinson’s patients as they go about their daily routines.

Analyses of sensor results using one algorithm, in particular, were similar to an established test assessing tremor without being dependent on the time the test is given.

The study, “Wearable Sensors for Estimation of Parkinsonian Tremor Severity during Free Body Movements,” was published in Sensors.

Resting tremor, or the rhythmic shaking of muscles while relaxed, is among the motor symptoms of Parkinson’s disease (PD), and some patients also have active tremor, or shaking while engaged in voluntary muscle movement. Others motor symptoms are slowness of movement (bradykinesia), rigidity, and problems with posture, balance, and gait.

Currently, Parkinson’s motor symptoms are assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III, scores of whose tests (like the finger-to-nose test) are evaluated by doctors. This test requires office visits where the tasks are performed, providing essentially only a snapshot of a person’s tremor experience in day-to-day life.

“A single, clinical examination in a doctor’s office often fails to capture a patient’s complete continuum of tremors in his or her routine daily life,” Behnaz Ghoraani, PhD, an assistant professor at Florida Atlantic University’s (FAU) Institute for Sensing and Embedded Network Systems (I-SENSE) and FAU’s Brain Institute (I-BRAIN), and lead author of the study, said in a press release.

“Wearable sensors, combined with machine-learning algorithms, can be used at home or elsewhere to estimate a patient’s severity rating of tremors based on the way that it manifests itself in movement patterns,” Ghoraani added.

Investigators developed two distinct machine-learning algorithms that, when combined with wearable sensors, could estimate total Parkinsonian tremor as patients performed a variety of free body movements.

In a collaboration between FAU, the Icahn School of Medicine at Mount Sinai and the University of Rochester Medical Center, researchers developed two algorithms: gradient tree boosting and long short-term memory (LSTM)-based deep learning. These tools can estimate tremor severity both in a resting and action state.  

A total of 24 Parkinson’s patients (10 women and 14 men; mean age, 58.9) had data on their movements recorded in two studies.

“In both protocols, the subjects stopped their medication the night before the experiment, and the experiment started in the morning. Yet, if the subjects were unable to withdraw their medication overnight, they came to the laboratory near the time of a scheduled dose of their PD medication,” the researchers noted.

For the experiment, doctors placed one motion sensor (consisting of a gyroscope and an accelerometer) on patients’ wrist and another on the ankle of the most disease-affected body side. Movement was recorded as they went about daily life activities.

Fifteen individuals were instructed to perform four rounds of specific activities, like walking, resting, eating, drinking, dressing, combing hair, putting groceries on a table, and cutting food. Motion data were recorded only while performing these activities.

Patients then took their routine “morning dose” of Parkinson’s medications. Later, they repeated the same activities at the start of every hour for up to four hours. For comparison purposes, standard UPDRS-based assessment were also given preformed every hour of the testing period before each round of daily life activities.

The other nine patients had their motion recorded continuously for the entire experiment. These people were instructed to cycle through six stations in a home-like setting, performing tasks like personal hygiene, dressing, eating, desk work, entertainment, and laundry. They took their medications after finishing a first round of activities, and when the treatment kicked in, they repeated the previous exercises. This set of activities lasted up to two hours, and the motor part of UPDRS (Part III) was assessed before and after the experiment.

“The data from the 15 subjects who performed rounds of specific [activities of daily living] was used to train the [artificial intelligence] models, and the data from the remaining nine subjects who performed continuous [daily life activities] were held out for testing the models,” the researchers wrote.

Results revealed the gradient tree boosting method estimated total tremor as well as resting tremor with high accuracy, and in most cases, with the same results found by doctors scoring UPDRS Part III.

Importantly, gradient tree boosting-based sensors were able to detect decreases in tremors after patients took their medication, even in cases where results did not match total tremor sub-scores from the UPDRS assessments. The LSTM-based algorithm was less effective in doing the same.

“These results indicate that our approach holds great promise in providing a full spectrum of the patients’ tremor from continuous monitoring of the subjects’ movement in their natural environment,” the researchers wrote.

“It is especially interesting that the method we developed successfully detected hand and leg tremors using only one sensor on the wrist and ankle, respectively,” said Murtadha Hssayeni, a study co-author and a PhD student at FAU’s Department of Computer and Electrical Engineering and Computer Science.

The new gradient tree boosting algorithm combined with wearable sensor technology resulted  “in the highest correlation … reported in the literature when using unconstrained body movements’ data,” the researchers wrote.

“This finding is important because our method is able to provide a better temporal resolution to estimate tremors to provide a measure of the full spectrum of tremor changes over time,” Ghoraani added.

https://parkinsonsnewstoday.com/2019/11/04/wearable-sensors-and-algorithm-measure-parkinsonian-tremor-severity-daily-life-study/

Free weekly sessions aim to aid those with Parkinson’s

SUN GAZETTE NEWSPAPERS     November 4, 2019

Bowen McCauley Dance Company is offering free weekly classes for those with Parkinson’s disease and their care partners on Wednesdays at 4:30 p.m. at Kenmore Middle School.

The initiative is based on the “Dance for PD” program of Mark Morris Dance Group, designed so classes are safe, beneficial and enjoyable.

There is no charge and no registration is required; previous dance experience is not required.

For information, call (703) 910-5175 or e-mail dance@bmdc.org.

https://www.insidenova.com/health/free-weekly-sessions-aim-to-aid-those-with-parkinson-s/article_b7d7393e-fe41-11e9-a163-ff9d846dd17d.html

Clinical Challenges: REM Sleep Disorder as Parkinson's Precursor

 November 4, 2019   Salynn Boyles

    RBD may be earliest marker of the movement disorder

A relatively rare sleep disorder characterized by acting out dreams during REM sleep -- often violently -- is closely linked to the movement disorder Parkinson's disease and may warn of Parkinson's decades before diagnosis.

People with REM sleep behavior disorder (RBD) do not have normal muscle paralysis during the dream phase of sleep. The loss of motor inhibition is generally accompanied by often frightening dreams, which are "acted out" with arm flailing, kicking, punching, and sometimes, screaming and shouting.

"If patients are running in their dream, they 'run' in their beds. If they are fighting with someone in their dream, their arms may flail wildly. This can be dangerous for the patient and the patient's bed partner," Marina Romero-Ramos, PhD, of Aarhus University in Denmark, told MedPage Today.

The prevalence of RBD has been estimated to be from 0.38% to 1% in the general population, but the sleep disorder is much more common in patients with Parkinson's disease.

In one study, 69% of patients with a diagnosis of Parkinson's reported symptoms consistent with RBD, while no increased risk was seen in patients with the related movement disorders essential tremor and restless leg syndrome.

Even more significant, a large percentage of people with RBD go on to develop Parkinson's years and even decades later, said Miranda Lim, MD, PhD, of the VA Portland Health Care System in Oregon.

"It is widely believed that RBD is one of the earliest markers of Parkinson's," she told MedPage Today. "Some people convert after a few years and some convert after many decades. It's possible that everyone with RBD would develop Parkinson's if they lived long enough, but we don't yet know this."

In a multicenter study published in Brain last spring, researchers predicted the risk of developing Parkinson's and related neurodegenerative disease in a group of 1,280 patients with idiopathic RBD (average age of 66.3; 82.5% of whom were male) treated at 24 centers.

Dementia and Parkinson's risk was estimated using the Kaplan-Meir analysis, and the researchers used the Cox proportional hazards analysis to further assess risk.

During an average follow-up of 3.6 years (range of 1-19), the overall conversion rate from RBD to documented neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12 years of follow-up.

Baseline abnormal quantitative motor testing was a risk factor for conversion (hazard ratio [HR] = 3.16), as was olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), color vision abnormality (HR = 1.69), and older age (HR = 1.54).

Patient characteristics that were not significantly predictive of conversion to Parkinson's or Parkinson's-related dementia (dementia with Lewy bodies) included sex, daytime somnolence, insomnia, restless legs syndrome, obstructive sleep apnea, urinary dysfunction, depression, and anxiety.

The study, which included the largest cohort with idiopathic RBD ever, confirmed "a high risk of phenoconversion to overt neurodegenerative disease," wrote Ronald Postuma, MD, MSc, of McGill University in Montreal, and colleagues.

Another recently published trial by Lim, et al. showed that military veterans with post-traumatic stress disorder (PTSD) had a much higher prevalence of RBD than the general public.

In all, 394 veterans (94% male, average age of 54.4±15.5), prospectively/cross-sectionally recruited from the VA Portland Health Care System, underwent overnight sleep studies from 2015 to 2017 to assess muscle activity during REM sleep.

The overall rate of RBD was 9%. The prevalence of RBD increased to 15% among study participants with PTSD, and to 21% among study subjects with both PTSD and a traumatic brain injury.

Given the strong association between RBD, Parkinson's, and other age-related neurodegenerative diseases "it remains unclear whether or not the association between RBD and traumatic brain injury/PTSD increases the risk of similar long-term neurologic sequelae," Lim and colleagues wrote in SLEEP.

Lim said the study cohort will be followed in the hopes that longitudinal analysis will help answer this question.

"Of course these studies will take a long time -- probably decades," she said.

She added that patients with RBD could represent an important study group in the ongoing search for treatments that will prevent Parkinson's or dramatically slow its progression.

"The problem with current trials is that by the time people have traditional symptoms of Parkinson's, most of the dopamine neurons in the brain are already lost," she told MedPage Today. "But people with RBD may be years or even decades away from developing these symptoms."

Recently published research by Romero-Ramos and colleagues suggest that the immune system may play a key role in Parkinson's disease.

When the researchers exposed blood samples from 29 Parkinson's patients and 20 control subjects to the protein alpha-synuclein, they discovered that the blood from the Parkinson's patients was worse at regulating immune markers on the cell surface. The patients' blood also secreted fewer anti-inflammatory cytokines.

"Parkinson's disease peripheral immune cells shed lower in-vitro levels of soluble CD163, which suggests a less responsive monocytic population and/or an activation status different from control cells," the team wrote.

The findings suggest that it might be possible to prevent or slow the degeneration of neurons related to Parkinson's by regulating the immune system, Romero-Ramos said.

And patients with REM sleep behavior disorder may be the perfect subjects to test the hypothesis.

"RBD is a disease where protein alpha-synuclein is aggregated, so we consider this very, very early stage Parkinson's," she told MedPage Today, adding that her research team is now studying the immune systems of patients with the sleep disorder.

https://www.medpagetoday.com/clinical-challenges/chest-sleep/83110

Urine Biomarker Correlates With Parkinson's Risk Factor Gene

November 04, 2019      Daniel M. Keller, PhD 

NICE, France — Levels of a group of urinary markers correlate with the LRRK2G2019S gain-of-kinase function gene mutation, a common cause of dominantly inherited Parkinson's disease (PD), a new study shows.

The markers are isoforms of the lipid bis(monoacylglycerol) phosphate (BMP), and one correlated with cognitive decline among carriers of the LRRK2mutation but not PD.

"BMP levels are highly correlated with LRRK2 mutation status, which is significantly elevated in LRRK2 carriers compared to noncarriers," Roy Alcalay, MD, Columbia University, New York City, reported during a guided poster tour at the 2019 International Congress of Parkinson's Disease and Movement Disorders. The study was funded by the Michael J. Fox Foundation.

"And interestingly, at least for some of the isoforms [of BMP], it's even further elevated in LRRK2 patients with Parkinson's compared to LRRK2 patients without Parkinson's," he said.

BMPs are lipids localized in the inner membranes of late endosomes and particularly in lysosomes. BMP elevation may be a biomarker of lysosomal dysfunction.

The study used biobanked samples from 80 participants who were part of the LRRK2 Cohort Consortium (LCC), frequency-matched for the study by sex, disease duration, and age of onset. Participants included:

• 20 PD patients with the LRRK2 G2019S mutation (PD+ LRRK2+)
• 20 idiopathic PD patients without the mutation (PD+ LRRK2-)
• 20 mutation carriers not manifesting PD (PD- LRRK2+)
• 20 healthy individuals without the mutation (PD- LRRK2-)

Fifty-four bioactive lipids, including BMP, were measured in these samples.

A second biobanked cohort, the Columbia University Irving Medical Center (CUIMC) cohort, comprised clinical and genetic data, including motor and cognitive measures, from 116 individuals at a single site. These samples were analyzed for BMP levels. Because BMP data were comparable in both sample sets, the data were combined, and all values were normalized for creatinine levels.

For the four urine BMP analytes assayed, higher levels were found in samples from participants who carried the LRRK2 G2019S mutation, and among those, the highest levels were in samples from participants who were PD-positive. But even for PD-negative samples, BMP levels were higher in samples from participants carrying the mutation.

Table 1. Median Urine BMP Isoform Levels in the Combined Cohort

Levels (range)	PD+LRRK2+ (n = 45)	PD+LRRK2- (n = 60)	PD-LRRK2+ (n = 36)	PD-LRRK2- (n = 55)	P
Total di-18:1-BMP	5.81 (0-30.85)	2.31 (0-19.1)	4.91 (1.03-24.9)	1.63 (0-8.0)	< .0001
Total di-22:6-BMP	37.4 (9.36-380.92)	10.5 (1.13-100.01)	31.5 (5.16-190.3)	9.23 (0-67.0)	.0004
2,2' di-18:1-BMP	4.25 (0-23.42)	1.39 (0-14.84)	3.15 (0.75-20.12)	1.62 (0-8.92)	< .0001
2,2' di-22:6-BMP	26.2 (6.73-302.8)	6.15 (0.59-72.02)	20.5 (3.29-142.9)	5.38 (0-42.26)	< .0001

BMP = bis(monoacylglycerol) phosphate

 Researchers tested the association of two disease severity indicators, the Montreal Cognitive Assessment (MoCA) and Unified Parkinson's Disease Rating Scale-III (UPDRS-III), with BMP isoform levels in linear regression models.

"When you took the LRRK2 patients without Parkinson's, for at least one of the isoforms, the 22:6, higher levels were associated with...poorer MoCA performance. So it was argued that maybe LRRK2 BMP levels can be correlated with disease severity," Alcalay said.

When adjusted for age, sex, disease duration, years of education, and LRRK2status, normalized total di-22:6-BMP and normalized 2,2' di-22:6-BMP levels were significantly associated with MoCA scores (P = .0461 and P = .0104, respectively).

None of the isoform levels was significantly associated with UPDRS-III scores.

Alcalay cautioned that one cannot use BMP levels "to say if someone is an LRRK2 carrier or not, or if they have Parkinson's or not," but if correlated with other biomarkers, BMP could serve as a "target engagement" in drug trials in PD "to see if the drug actually reduces LRRK2 activity in people who participated in LRRK2 studies."

He suggested that, if given longitudinal samples, BMP levels could possibly be used as a biomarker for disease severity in LRRK2 mutation carriers.

Poster tour co-leader Susan Fox, MB ChB, PhD, of the University Health Network, Toronto, Ontario, Canada, asked Alcalay if the researchers correlated BMP levels only with the G2019S mutation in LRRK2 or if levels also correlated with other LRRK2 mutations.

Alcalay said they only looked at the G2019S mutation in LRRK2 but also looked at mutation carriers of the GBA gene, another risk factor for PD. Because the number of GBA mutation carriers in the study was small, they did not report BMP levels, but he revealed that levels appeared to be decreased in these patients.

In an interview, Alcalay said BMP levels could be useful in a couple of ways. The first way is to target therapy. Second, if a therapy worked in patients with an LRRK2 mutation, one could investigate if it was effective in PD patients without LRRK2 mutations but high BMP levels, the rationale being that the LRRK2 pathway might be activated in different ways and therefore make such patients good candidates for therapies directed at LRRK2.

The second question was whether BMP is just a marker of lysosome dysfunction or if the dysfunction is part of the pathophysiology of PD. Calling it "a great question," Alcalay said currently there is no answer, adding, "We don't really explain here, and we don't really know why BMP is elevated in LRRK2mutation carriers or why it goes down with LRRK2 inhibitors...but the biology of it, I think there is more to learn."

He offered that more mechanistic studies, beginning in animal models, should shed light on the answer.

Fox commented to Medscape Medical News that the study was well designed and is from a good research group. Specifically addressing the study, she said, "If you could measure something in the urine...I think that's good. It's much easier than doing a lumbar puncture." However, she questioned whether BMP correlates with disease.

Co-tour leader Michael Schwarzschild, MD, PhD, of Massachusetts General Hospital, Boston, said the study reflects "some of the most exciting developments towards precision medicine, particularly gene-targeted therapies for disease modification and Parkinson's disease, LRRK2 and GBAbeing of particular focus." Biomarkers are some of the tools that will "help us better understand the targets and patient populations, and how to find them and how to follow them."

Similarly, he said that if BMP levels are a reflection of the pathophysiology of PD and if there is a drug that is designed to compensate for it, then the biomarker could be a simple, accessible measure that will facilitate trials.

"So I thought it was encouraging that you can get a hook at a molecular level. It's something so accessible, that's relevant — but why is it relevant? What's the biology? How reproducible is it? Is it responsive to therapies that target that pathway? [These are] all sort of next-step questions that [Alcalay] seems poised to pursue," he said.

Looking ahead, Fox said, "If you can expand what's found in a very well-defined homogeneous population of LRRK2 into the general PD population, that's where that's the winner."

International Congress of Parkinson's Disease and Movement Disorders 2019. Abstract #553. Presented September 23, 2019.

https://www.medscape.com/viewarticle/920818#vp_2

Enzyme Discovery May Put Brakes on Parkinson’s Disease

November 4, 2019

Researchers at the University of Dundee have identified an enzyme that inhibits the protein kinase product of a gene known as LRRK2, mutations in which are the common genetic cause of Parkinson’s disease (PD). The researchers’ laboratory studies showed that the inhibitory enzyme, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins. The researchers suggest that the findings could lead to new therapeutic and preventive strategies against Parkinson’s disease.

“Parkinson’s is like a runaway train—at present we have no way of putting the brakes on to slow it down, let alone stop it,” commented Dario Alessi, PhD, director of the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU) in the School of Life Sciences. “This new enzyme we have found acts as the brakes in the pathway that causes Parkinson’s in humans.” Alessi’s team, together with collaborators at Stanford University School of Medicine, report their findings in eLife, in a paper titled, “PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins.”

LRRK2 is a large multidomain protein kinase enzyme. Mutations in the LRRK2 gene that hyperactivate the protein cause Parkinson’s disease, the authors stated. “Mutations in LRRK2 are one of the most common genetic causes of familial Parkinson’s comprising ~5% of familial Parkinson’s, and ~1% of sporadic Parkinson’s patients. In terms of clinical presentation and late age of onset, LRRK2 mediated Parkinson’s closely resembles the common sporadic form of the disease affecting the vast majority of patients.” While the G2019S mutation is the most common LRRK2 mutation there is also evidence that the LRRK2 pathways is hyperactivated in some patients with idiopathic PD.

Accumulating evidence of a role for LRRK2 signaling in Parkinson’s disease has directed one avenue for drug development. “Pharmaceutical companies have developed LRRK2 inhibitors for treatment and prevention of PD and clinical trials have commenced and/or are planned,” the team continued. Studies have shown that LRRK2 phosphorylates a subgroup of Rab proteins, and while protein phosphatase enzymes that act on LRRK2-phosphorylated Rab proteins are known to exist and appear highly active, these enzymes haven’t yet been identified, Alessi and colleagues noted. Much of what is already known about the LRRK pathway has been discovered by the Dundee team, and the investigators set up a series of siRNA screens to identify and characterize the protein phosphatase, or phosphatases, that counteract LRRK2 signaling by dephosphorylating LRRK2-modified Rab proteins.

One of the top hits in all three screens was the enzyme PPM1H, which exhibited a remarkable ability to reverse the biology triggered by LRRK2. “Repeat studies in multiple experiments confirmed that siRNA mediated depletion of PPM1H increased Rab10 phosphorylation, without affecting overall levels of Rab10 or LRRK2,” the authors wrote. Subsequent studies showed that overexpression of PPM1H inhibited LRRK2-mediated Rab protein phosphorylation in cell lines. Conversely, using CRISPR-Cas9 editing to knock out full length PPM1H enhanced Rab10 protein phosphorylation. “Basal levels of Rab10 phosphorylation was increased 2–5-fold in 10 independent knock-out cell lines that we examined,” the scientists continued.The Dundee team had previously shown that pathogenic LRRK2 suppresses cilia formation in cell culture and in the mouse brain, through a process that requires proteins including Rab10. Through a series of experiments the researchers also demonstrated that endogenous PPM1H protein contributes to the regulation of cilia formation in cultured cells, “… and confirms a role for wild-type LRRK2 protein in this important cellular process.”

They claim that their findings provide “compelling evidence” that PPM1H acts to dephosphorylate Rab proteins in vivo, and so counteract LRRK2 signaling. “In future work, it will be important to explore whether PPM1H contributes to PD risk,” they stated. “It would be critical to explore whether increased expression or activity of PPM enzymes protects patients with LRRK2 mutations from developing PD by enhancing Rab protein dephosphorylation. Conversely, reduced expression or activity of PPM1H phosphatase would be expected to promote Rab protein phosphorylation and enhance PD risk. Targeting PPM1H to increase its activity or expression in order to promote Rab protein dephosphorylation could be explored as a therapeutic strategy for preventing and/or treating LRRK2-mediated PD.”

“We have known for many years that the LRRK2 pathway is a major driver behind Parkinson’s but the concept of developing an activator of the PPM1H system to treat the disease is completely new, Alessi sad. “This finding opens the door for a new chemical approach to the search for Parkinson’s treatments … In terms of the current approach, Plan A is to develop a drug to inhibit LRRK2 but even once this is done we don’t know how well such a drug will be tolerated in the body so we are also looking for other ways to switch off this pathway. The purpose of this research was to find an enzyme that naturally stops LRRK2 by mediating these toxic pathways.

This is professor Dario Alessi, PhD. 

[University of Dundee]

The development of any form of drug derived from PPM1H is still years away, but the Alessi team and collaborators have started to work with the University’s Drug Discovery Unit to search for a compound that would switch the enzyme on for the treatment of Parkinson’s. “It would appear that the PPM1H enzyme is present in all people and it is not missing in patients with Parkinson’s so if we can find a way of switching this on then it theoretically could benefit all,” Alessi noted. “It also raises another exciting question that we want to study—is PPM1H higher in the brain of certain people and, if so, is this protecting them against Parkinson’s?”

“By making this discovery, we are now in a position to work with pharmaceutical companies and the Drug Discovery Unit here at Dundee to develop compounds that would switch on this enzyme. This will be challenging work but if we can identify appropriate drug-like molecules then the next stage would be to test them in cells and in animal models to see if they do indeed switch off this pathway. If that works it would be certain to stimulate further preclinical activity and could potentially lead to a new way to treat Parkinson’s. We have a lot of obstacles to overcome before we get to that point but this is a major discovery for us."

https://www.genengnews.com/news/enzyme-discovery-may-put-brakes-on-parkinsons-disease/

Synthetic compound provides fast screening for potential drugs

NOVEMBER 4, 2019    by Okayama University

The fluorescence from compound 10 increases when an RXR targeting ligand displaces it, making it a useful indicator for ligand activity in assays. Credit: Okayama University

A simple assay may benefit drug discovery for treating diabetes, Parkinson's, and Alzheimers disease, as well as studies of functional food and endocrine disruptor report researchers at Okayama University in the Journal of Medicinal Chemistry. The assay hinges on a synthetic compound that allows faster screening with fewer hardware resource requirements than existing methods.

Retinoid X receptors (RXRs) are a type of nuclear receptor—proteins that regulate an organism's development, homeostasis and metabolism. They usually operate as heterodimers alongside other proteins and receptors, so the ligands targeting them are key to controlling their activity. RXR activators have attracted particular interest recently because of their potential to treat diabetes, Alzheimers and Parkinsons disease. They are also associated with functional foods and processes by which environmental pollutants damage health. However, methods for screening compounds for their potential RXR targeting ligand activity have so far proved slow and awkward. Associate Professor KAKUTA Hiroki at University of Okayama Graduate School of Medicine and Shogo Nakano at the University of Shizuoka in Japan, and their colleagues have now demonstrated an assay based on a synthetic compound CU-6PMN—referred to as 10—that can screen for RXR targeting ligand activity in hours instead of days with no complex equipment or radioactive isotopes needed.

The researchers based the chemical structure of synthetic compound 10, on the RXR activator CD3254, referred to as compound 9. "Because 9 has a cinnamic acid structure, we anticipated that this structure could be developed toward an umbelliferone structure," they explain in their report of the work. The significance of umbelliferone is its fluorescence. Not only is the fluorescence of umbelliferone relatively easy to detect—widely available filter sets can detect it—but the compound can also be modified so that its fluorescence intensity increases in aqueous environments. This means that if a compositely binding RXR ligand displaces the receptor bound compound, the fluorophore will be exposed to a more aqueous environment, its fluorescence will increase, and the activity of the ligand can be detected.

With compound 10 the researchers showed they could detect RXR targeting ligand activity in just a few hours with standard fluorescence microplate readers and no need for complicated processes. In their report they conclude, "We believe it will be useful not only for identifying RXR binders in drug discovery studies but also for studies of functional foods and endocrine disruptors, though it should be noted that fluorescence-based assays often suffer from interference when used to screen natural products."

Nuclear receptor activity mechanisms

Nuclear receptors are found in cells. They sense the presence of small molecules such as steroid and thyroid hormones and regulate the expression of genes to control bodily processes. The human body has 48 types of nuclear receptor. The RXR activator bexarotene is already used clinically to treat cutaneous T cell lymphoma, and recent studies have recommended its potential for treating diabetes, Alzheimer's disease, and Parkinson's disease. Polyunsaturated fatty acids including docosahexaenoic acid (DHA) are naturally occurring RXR targeting ligands and are linked to improved memory and metabolic syndrome. Conversely the impact of environmental polluters on nuclear receptors can inhibit their interaction with hormones and disrupt the endocrine system.

Current assay techniques

To test for the presence and activity of substances, researchers in medicine, pharmacology and environmental and molecular biology use assays. Previous assays for RXR targeting ligand activity have also used fluorescence, but they have had drawbacks. Those based on time-resolved fluorescence resonance energy transfer, require a special reader plate, while others have been based on quenching the autofluorescence of the molecule tryptophan, which has a weak autofluorescence signal at a wavelength that standard readers cannot detect. Alternative assays have used reporter genes and take 3-4 days to detect ligandactivity, or they have used radioisotope labeled ligands, where the issues that surround use of radioactive isotopes further complicate an already complex procedure.

More information: Shoya Yamada et al. Competitive Binding Assay with an Umbelliferone-Based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening, Journal of Medicinal Chemistry(2019). DOI: 10.1021/acs.jmedchem.9b00995

Journal information: Journal of Medicinal Chemistry 

Provided by Okayama University 

https://medicalxpress.com/parkinsons-disease-news/