A YouTube binge helped invent a new way to diagnose Parkinson's

JUNE 10, 2019    By AMIT KATWALA

Faceprint founder Erin Smith started working on her diagnostic tech, which tracks the development of Parkinson's through facial expressions, after watching videos of Michael J Fox

Health-tech startup FacePrint aims to diagnose Parkinson’s disease from Facebook photos, but it started with a journey down the YouTube rabbit hole.

Around three years ago, founder Erin Smith, then a high-school student in Kansas, was watching an interview with actor Michael J Fox, the star of Back to the Futurewho was diagnosed with Parkinson’s disease at the age of 29. Smith, who is now 19, noticed something odd about the way Fox smiled. His facial expressions seemed forced and emotionally distant, even in response to genuine emotions.

“Michael J Fox is a really interesting case study, because you can go back to the films he was in, and create kind of a timeline of when these facial differences started to occur,” Smith says. As she clicked through and watched more interviews with people with Parkinson’s – a degenerative brain disorder which can cause tremors and slurred speech – an idea started to form.

A few years prior, Smith had been obsessed with a prime-time detective show called Lie to Me, which starred Tim Roth as Cal Lightman, a scientist who was an expert at reading people’s expressions. The show was loosely based on the work of psychologist Paul Ekman, who has spent decades analysing and cataloguing “micro-expressions” – tiny gestures and movements of the facial muscles which are too quick for most people to notice.

Smith spent hours reading blogs about the show and the scientific research it was based on. “For me, there was just a fundamental curiosity about what else the science behind facial expressions could reveal,” she says.

She decided to run a controlled study. After writing to a local Parkinson’s support group, she spent her spring break running around her hometown with a backpack and two laptops, visiting local people with Parkinson’s as well as healthy control subjects to capture videos of their facial expressions. Smith collected data on both spontaneous expressions (in response to video clips), and posed expressions (where her subjects tried to mirror expressions they were shown).

Once she had collected the data, she needed to analyse it. “I hadn’t coded before, and basically locked myself in my house and got a tonne of different Coding for Dummies books to teach myself the fundamentals,” she says. “And then it was just building and learning as I went, continuously refining the technology and improving my own skills.”

With the help of Affdex, an off-the-shelf facial recognition software package, she was able to demonstrate that there was a measurable difference in facial expressions between people with Parkinson’s and people without. “It was all honestly just driven by curiosity, I was really captivated with this idea,” she says. “After that, it was the human element that motivated me to scale up the process and continue the research.”

Smith contacted the Michael J Fox Foundation to tell them about her work, and they helped her run two more pilot studies. “In order to really get the most out of these differences and develop prediction and detection and monitoring algorithms, I knew I needed to scale up data collection,” she explains.

Her technology is now the basis for FacePrint, which is still based in San Francisco (and which won the startup showcase at WIRED Health in March). Smith has deferred her offer of a place at Stanford University to work on the company, with the help of a two-year, $100,000 (£79,000) fellowship from the Thiel Foundation, funded by the PayPal billionaire Peter Thiel.

FacePrint is now launching clinical trials, and Smith is working with software engineers to create an automated web or smartphone-based detection and monitoring system, which she hopes will help cut down on rates of misdiagnosis – a particular problem in a primary care setting. The company is building a five-minute facial expressions test that can be administered at home or at the doctor’s, via a smartphone, laptop, or pretty much any device with a camera. Eventually, Smith says, doctors could wear Google Glass-style headsets which could detect signs of Parkinson’s during a normal conversation.

The facial recognition software that FacePrint is built on is also compatible with social media platforms. “Ultimately, it would be possible to integrate FacePrint into those systems, and turn social media platforms into a really powerful healthcare tool,” says Smith – although she stresses the need to do so in an ethical way. (You wouldn’t want a sudden push notification: “You might have Parkinson’s.”)

Smith’s ambitions stretch beyond just one disease. By early June, she plans to have launched Project FacePrint, which will extend facial impairment research beyond Parkinson’s through a crowdsourced citizen science effort. “Through the process of designing this, I’ve gained a really immersive view into the healthcare system,” Smith says. “My mission is to redesign different elements of healthcare. For me, I view this technology as one piece of a larger whole.”

https://www.wired.co.uk/article/parkinsons-disease-diagnosis-faceprint?fbclid=IwAR1DN9WsM5H2ANa7VizoHw60SlResxtrCBkDXGYLfgaE5crOMPRL7OQeOr4

The Link Between Compassionate Support and Wellness

JUNE 14, 2019 BY DR. C

It has been rough going recently, after I acquired a “legally blind” diagnosis on top of Parkinson’s disease. It has been a month, and part of the reason I am back to column writing so soon is because of the compassionate support I received, which was freely given. It has made a big difference in my life. This compassionate support has bolstered my wellness program and given me the added strength I needed to move forward.

People speak of wellness as some sort of bonus you get from doing something because it’s “good for you,” like eating vegetables or walking 10,000 steps a day. But healthful practices are not the only factor in the wellness process. The wellness that comes from compassionate support is more than that. 

When support is given in a truly compassionate way, it reflects not only on the act of support, but also on the possibility that we can be a “better self.” It doesn’t matter how bad things appear because compassionate support can make things better. It works.

There are lots of ways to block yourself from connecting to the compassion others offer. Sometimes, it seems easier to give than to receive. This month, I didn’t want to go to the local Parkinson’s support group. I felt like a failure, to everyone else and to myself. The pain and suffering I was going through created a wall between me and the rest of the world. 

My partner of almost 50 years convinced me to go. Allowing myself to be vulnerable, to let down those walls and enjoy the support group, also allowed me to feel this potential for the betterment of mankind. I connected to that for my personal well-being. Moaning about how terrible I feel doesn’t get me anywhere. I am trying to focus on the here and now, to keep a positive attitude about tomorrow.

Over the past four years, my partner and I have moved to a new house that is more ADA-accessible, changed career focus, rebuilt our caregiver/social network, and dealt with each untoward event that has popped up along the way. My partner walked with me through all of this while having her own medical issues. Often fatigued and occasionally overwhelmed, she fought hard to improve our quality of life. This included kicking me in the butt occasionally, and being firm about the importance of continuing to engage in life.

There is much research that lends credence to this idea that humans helping one another — sharing in the process of compassionate support — can make a difference in wellness. A recent study showed that a stronger purpose in life was associated with lower all-cause mortality. Several interventions have been clinically reviewed, including well-being therapy, that demonstrated improvements in purpose in life, quality of life, and various health outcomes.

The “O” in CHRONDI is for “Others.” It speaks to the interconnectedness we have with each other, connections that can help with our wellness. This is not about some supernatural phenomena or “butterfly effect.” Rather, it is about a human relationship phenomenon that exists to share a flow moment in time. It is the experience of gratification after allowing myself to embrace the compassion being given. The compassion given and received (well-being experienced phenomenon) is a fundamental part of the relationship I call the healing relationship. 

There can be resistance to the healing relationship that is connected to compassionate support. Connectedness doesn’t usurp identity. I sit on the island of individuality often. The idea of self has special meaning for me. It’s the “I” in CHRONDI. When it comes to wellness, that island is the last place I want to be.

***

I want to add a special note of recognition and gratitude to my first-line editor, Robin Ketchen; the BioNews Services team, especially Brad Dell and Dave Boddiger; my family and friends; the New London and Concord Parkinson’s support groups; and all those readers of my column whose comments were so encouraging for me to continue writing. A special hug to my wife, who reminds me of where I need to be, helps me get to the destination, and has supported the “journey” for all these decades. 

***

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/2019/06/14/compassionate-support-wellness-healing-relationship/

MJFF Assists Nitrome Biosciences’ Pursuit of Parkinson’s Therapies

JUNE 14, 2019 BY MARY CHAPMAN 

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has awarded Nitrome Biosciences a Target Advancement grant to further the company’s development of therapies targeting Parkinson’s disease.

Specifically, the grant will be used to further Nitrome’s biological studies of a new Parkinson’s drug target.

The therapies are aimed at inhibiting a newly identified enzyme the company calls synuclein nitrase. The company said the enzyme causes or accelerates the nitration — a type of chemical modification caused by cellular stress — and aggregation of alpha-synuclein, a hallmark of Parkinson’s disease. At length, Nitrome will test whether an impeded enzyme can slow or stop Parkinson’s progression.

“We’re immensely grateful to MJFF for awarding this grant to Nitrome. This provides not only critically needed support but also shows interest in our unique approach to Parkinson’s disease drug development,” Irene Griswold-Prenner, PhD, said in a press release. Griswold-Prenner is Nitrome’s founder and CEO. “Additionally, the close connection with MJFF personnel provides important feedback as well as access to information, disease models and reagents.”

MJFF associate director of research programs, Luis M. Oliveira, PhD, calls the alpha-synuclein pathway a “compelling” target for development of Parkinson’s treatments.

“We are glad to support this study to mediate pathology and advance toward treatments that slow or stop disease progression,” he said.

Accumulation of alpha-synuclein, the chief component of Parkinson’s disease Lewy bodies, is found not only in the brain, but in the peripheral autonomic nervous system, which ultimately affects breathing and digestion.

A modified — nitrated — form of the protein can be found in salivary gland tissue of Parkinson’s patients. Because nitrated alpha-synuclein exists in early stages of PD, it could be a promising disease biomarker.

While starting with Parkinson’s, the company plans to use its discovery of the newly identified enzyme class to develop disease-modifying compounds for other neurodegenerative disorders, plus diabetes, heart disease and cancer.

The MJFF is the world’s largest nonprofit funder of Parkinson’s investigations. Its Target Advancement Program focuses on the identification of proteins and pathways involved in the onset and progression of the disease. Typically, such grants are for 12 to 18 months and are valued at up to $150,000. The amount of this grant was undisclosed.

“Highly nitrated and misfolded proteins play important roles in multiple neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis,” said Ephraim Heller, chairman of Nitrome’s board of directors. “Nitrome will deploy its platform technology to develop therapies for multiple diseases involving enzymatic protein nitration.”

According to the MJFF, nearly one million U.S. residents will be living with Parkinson’s by 2020. The disease affects 10 million individuals globally.

https://parkinsonsnewstoday.com/2019/06/14/mjff-assists-nitrome-biosciences-parkinsons-disease-therapies/

Midbrain Area Measurements Can Be Used to Distinguish Parkinson’s From PSP, Study Says

 JUNE 14, 2019 BY JOANA CARVALHO  

Midbrain area measurements can be used to distinguish patients with Parkinson’s disease from those with progressive supranuclear palsy, a study finds.

The study, “Midbrain area for differentiating Parkinson’s disease from progressive supranuclear palsy,” was published in Clinical Neurology and Neurosurgery.

Progressive supranuclear palsy (PSP), the second most common Parkinsonian syndrome after Parkinson’s disease, is characterized by gait, balance, speech, vision, behavioral, and cognitive impairments. Despite recent advancements in brain imaging techniques, distinguishing people with Parkinson’s from those with PSP at the earliest stages of the disorders is still challenging for clinicians.

To learn more, researchers from the Iran University of Medical Sciences and the Tehran University of Medical Sciences set out to assess whether midbrain area measurements could be used to differential people with Parkinson’s from those with PSP. The midbrain is the region connecting the spinal cord to the brain, and plays key functions in motor movement, and in auditory and visual processing.

The team used a technique called transcranial sonography (TCS) — a non-invasive, fast, and inexpensive procedure used to visualize brain structures in people unable to undergo magnetic resonance imaging (MRI).

The study enrolled a total 35 patients, 18 of whom had been diagnosed with Parkinson’s, and 17 with PSP. Participants had an average age of 67.2 years, and had been living with their disorder for approximately five years before enrolling in the study.

The results showed that patients with Parkinson’s tended to have larger midbrain areas compared with those with PSP (average of 4.86 cm2 vs. 3.61 cm2). The differences in midbrain size between those with Parkinson’s and PSP remained significant even after researchers normalized the midbrain area values to each patient’s disease duration.

Further analyses demonstrated that using the midbrain area as a diagnostic tool to identify people with Parkinson’s disease had higher sensitivity and specificity compared with other regions of the brain, such as the diameter of the third ventricle. Specifically, the sensitivity was 83.3% vs. 38.9%, while the specificity was 70.6% vs. 18.0%, respectively.

The third ventricle is one of the cavities in the center of the brain that is filled with cerebrospinal fluid (the liquid that circulates in the brain and spinal cord).

However, the diameter of the third brain ventricle showed higher sensitivity and specificity compared with the midbrain area in identifying PSP patients (sensitivity of 82.0% vs. 29.0%; specificity of 62.0% vs. 17.0%, respectively).

“Midbrain area in patients with PD was wider than those with PSP that was not affected by disease duration. In comparison with SN [substantia nigra] hyperechogenoicity [higher response during transcranial sonography ] and third ventricle size, midbrain area was the most accurate index for differentiating PD and PSP by [transcranial sonography],” the scientists said.

https://parkinsonsnewstoday.com/2019/06/14/midbrain-area-measurements-distinguishes-patients-with-parkinsons-from-psp/

Modified protein can prevent Alzheimer's disease in mice

JUNE 14, 2019    by Shi En Kim, University of Chicago

Neurons in the brain of a mouse with Alzheimer's disease. New research from UChicago shows how a modified piece of one protein can prevent the disease in mice. Credit: NIH, Lennart Mucke, University of California, San Francisco

The amyloid precursor protein has always been vilified as a major cause of Alzheimer's disease. One of its fragments, the amyloid-beta peptide, can break off and accumulate in the brain, giving rise to the puffy white globs known as senile plaques that are a hallmark of the disease.

In a study published recently in the journal Cell Reports, however, researchers at the University of Chicago have redeemed APP as an unlikely hero, uncovering its extended role in brain signaling that can prevent the development of Alzheimer's disease in mice.

So, when does APP take on the mantle of hero versus swooping in as the villain in the tragic tale of Alzheimer's disease?

A long-neglected segment

For years, researchers have mainly paid attention to APP for the Aβ segment encoded in the amino acid sequence, like a dormant monster waiting to be unleashed. In the new research however, Angèle Parent, associate professor of neurobiology, and her team demonstrated that the other sections of a chopped-up APP strand matter too. One section plays a crucial role in consolidating spatiotemporal learning and memory in the brain, to the extent that it can prevent the onset of Alzheimer's disease under the right circumstances.

This long-neglected segment, when tethered to the cell membrane, can participate in a signaling mechanism that triggers the formation of new memories. To promote this tethering, Parent and team fashioned a sticky lipid anchor protein from natural APP. This modified APP segment, called the mAICD, is simple in structure but has enormous functional consequences. Six months after newborn mice were injected with a virus that encouraged a high expression of mAICD in the brain, the results were surprising.

These mice were genetically-engineered to be afflicted with aggressive Alzheimer's disease at a young age. Normally, they would have suffered from the advanced symptoms of the disease as young as six months old (equivalent to a young adult in humans), if not for the extra mAICD supplied by the researchers.

After the injection, Parent and her team tested the mice's ability to form spatiotemporal memories. Mice are curious but fickle creatures: familiarity is usually met with indifference. Equipped with a generous helping of mAICD, these mice successfully recalled—or ignored—objects and places previously explored. On the other hand, the control mice with Alzheimer's who expressed a less interactive version of mAICD, did not recognize supposedly familiar objects and locations at all. They were already gripped by the jaws of the disease.

"When we looked at the mice with the mAICD, they became almost normal," Parent said. It was as if these mice had never showed signs of Alzheimer's.

The dark horse jack-of-all-trades

This humble lipid anchor protein was able to keep Alzheimer's disease at bay in these mice, as long as its expression starts during the brain development stage. The researchers are currently investigating the effects of the same mAICD intervention in the brains of adult mice already afflicted with Alzheimer's.

"If you're are born with the Alzheimer's disease genes, you don't necessarily have memory problems when you're young. All that happens much later," Parent said. "By then, when you already have problems with your memory, will an mAICD boost be able to help you?"

Indeed, the diversity of APP's functions has exceeded the expectations of earlier researchers. By participating in complex nerve machinery, APP can stimulate the growth of new neurons and strengthen synaptic activity by triggering a series of events associated with memory consolidation. At the same time, APP may also produce Aβ to diminish these memories.

With its numerous and occasionally contradictory functions, this "all-purpose protein," as Parent fondly calls it, plays many roles: the villain, the redeemed hero, the dark horse, or a jack-of-all-trades. Nevertheless, Parent expects it to star as a coveted memory molecule for its power to form and erase memories in this Cinderella Story.

More information: Carole Deyts et al. APP-Mediated Signaling Prevents Memory Decline in Alzheimer's Disease Mouse Model, Cell Reports (2019). DOI: 10.1016/j.celrep.2019.03.087

Journal information: Cell Reports 

Provided by University of Chicago 

https://medicalxpress.com/news/2019-06-protein-alzheimer-disease-mice.html

Molecule May Halt Parkinson’s Progression, Study Using New Mouse Model Finds

 JUNE 13, 2019 BY CATARINA SILVA 

A molecule called anle138b was able to reduce toxic alpha-synuclein aggregates, or clumps, in the brain — a key event linked to Parkinson’s — and reverse motor symptomsassociated with the disease in a novel Parkinson’s mouse model.

The study, “Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model,” was published in Acta Neuropathologica. The work was funded by the charity Parkinson’s UK.

Many neurodegenerative disorders involve aggregation of misfolded (harmful) proteins in the brain. Parkinson’s is characterized by a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that damage and kill nerve cells, or neurons.

Anle138b has been shown to reduce toxic protein accumulation and delay disease progression in models of multiple system atrophy, Alzheimer’s disease and Parkinson’s.

Investigators from the University of Cambridge now evaluated the effects of anle138b in a new mouse model of Parkinson’s disease.

Although this molecule had previously been shown to reduce the clumping of proteins in other Parkinson’s models, the team wanted to understand its potential to treat the condition during its natural progression. To that end, they created a new mouse model that mimics the way alpha-synuclein gradually accumulates in specific areas of the brain, impairing neuronal communication and resulting in motor alterations.

The animals were nine months old before treatment initiation — around 46 human years. At the start of the treatment, the mice already showed low levels of dopamine in their striatum, a brain region involved in voluntary movement control that is severely affected in Parkinson’s. This reduction was associated with the onset of motor symptoms, including changes in gait that resembled some of the early motor symptoms seen in individuals with the disease.

However, the animals’ substantia nigra, another brain region involved in motor function that is also affected by the disease, had not yet been significantly damaged. Mice striatal (meaning “of the striatum”) and nigral (meaning “of the substantia nigra“) dopamine-producing neurons also exhibited alpha-synuclein aggregation.

Starting at nine months of age, mice were treated with anle138b for three months. Treatment reduced alpha-synuclein clumps, restored dopamine levels in the brain, and prevented dopaminergic nerve cell death. This was accompanied by gait improvements, suggesting that anle138b can effectively reverse, or at least halt, Parkinson’s progression.

These results indicated that “there is a window of time when it is possible to prevent [dopaminergic] neuronal death, even when striatal [dopaminergic] release is already impaired,” the researchers said. This means that if anle138b is given early on — before advanced nerve cell death — it may reduce  alpha-synuclein aggregates, potentially halting Parkinson’s progression.

“Our study demonstrates that by affecting early alpha-synuclein aggregation with the molecule anle138b in a novel transgenic mouse model, one can rescue the dopaminergic dysfunction and motor features that are typical of Parkinson’s,” Maria Grazia Spillantini, professor in the department of clinical neurosciences at the University of Cambridge, and the study’s lead researcher, said in a press release.

“The evidence from this early stage study builds on our understanding of how alpha-synuclein is involved in Parkinson’s and provides a new model that could unlock future treatments,” added Beckie Port, research manager at Parkinson’s UK.

https://parkinsonsnewstoday.com/2019/06/13/molecule-may-halt-parkinsons-progression-study-using-new-model-mouse-finds/

HYPE Protein Shows Promise in Treating Parkinson’s Disease, Research Shows

JUNE 13, 2019 BY PATRICIA INACIO, PHD 

The formation of alpha-synuclein aggregates in brain nerve cells (neurons) is thought to be one of the hallmarks of Parkinson disease. Researchers now have found that the activity of a single protein, called HYPE, may help halt alpha-synuclein accumulation and reduce its toxic outcomes, including neuronal death.

These findings, “Alpha-Synuclein Is a Target of Fic-Mediated Adenylylation/AMPylation: Possible Implications for Parkinson’s Disease,” were published recently in the Journal of Molecular Biology.

How Parkinson’s disease develops is still not well understood. However, evidence suggests that abnormal protein aggregates of alpha-synuclein, the main component of Parkinson’s disease hallmark Lewy bodies, are toxic and lead to neuronal death.

Clusters of misfolded (meaning altered structure) alpha-synuclein proteins also have been associated with disease severity. These aggregates lead to the formation of holes in the membranes of neurons, which affects their function and ability to communicate with other cells.

Previously, researchers had found that the HYPE protein can help cells cope with stress from misfolded proteins by promoting the addition of a chemical modification — called adenosine monophosphate (AMP), in a process known as AMPylation. They now asked whether HYPE also could play a role in Parkinson’s, specifically by modifying alpha-synuclein.

“Since HYPE plays such an important role in how cells deal with stress from misfolded proteins, we wondered whether diseases that result from protein misfolding were likely to need HYPE,” Seema Mattoo, PhD, an assistant professor of biological sciences at Purdue University and the study’s lead author, said in a press release.

“We know that in Parkinson’s disease, often the misfolded protein is [alpha-synuclein]. So we asked if HYPE could modify [alpha-synuclein], and if so, what are the consequences?,” Mattoo said.

Indeed, they found that HYPE is present in dopamine-producing neurons of the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in Parkinson’s disease – of rats.

Moreover, HYPE promoted the AMPylation of alpha-synuclein and this chemical modification decreased alpha-synuclein’s potential to aggregate.

When researchers looked at the protein under a microscope they found that HYPE changed its structure. While alpha-synuclein tends to twist, which may help promote aggregation, the new AMPylated protein did not twist as much, which may be why it aggregates less, Mattoo explained.

Importantly, AMPylation of alpha-synuclein also lessened the protein’s ability to make holes in neuronal membranes. “That means HYPE could possibly have a therapeutic effect on Parkinson’s disease,” Mattoo said.

Because alpha-synuclein is necessary for normal neuronal function, it has not been considered as a fit target for Parkinson’s therapy. However, these results open new possibilities.

“We’re all trying to apply a Band-Aid at the end of disease progression because we know aggregation causes the cells to become toxic, but how can we prevent that?” asked Mattoo. “There is still much to be understood mechanistically about it in the context of disease.”

Researchers now expect to expand their work to brain cells and animal models of Parkinson’s disease to validate their results.

“We’re in the early stages, but these results are giving us a new angle to look at potential therapeutics,” Mattoo said. “We’re trying to come up with drugs that could be used to manipulate HYPE’s activity. You could give them to patients who are starting to show signs of Parkinson’s or who are prone to having aggregated [alpha-synuclein]. That’s the direction we want to go.”

https://parkinsonsnewstoday.com/2019/06/13/hype-protein-treating-parkinsons-disease-study/

Gut microbes eat our medication

June 13, 2019    by Harvard University

Balskus has not only identified a species of bacteria responsible for consuming the Parkinson's drug levodopa, she figured out how to stop the microbe's meal. Credit: Kris Snibbe/Harvard Staff Photographer; Harvard University

The first time Vayu Maini Rekdal manipulated microbes, he made a decent sourdough bread. At the time, young Maini Rekdal, and most people who head to the kitchen to whip up a salad dressing, pop popcorn, ferment vegetables, or caramelize onions, did not consider the crucial chemical reactions behind these concoctions.

Even more crucial are the reactions that happen after the plates are clean. When a slice of sourdough travels through the digestive system, the trillions of microbes that live in our gut help the body break down that bread to absorb the nutrients. Since the human body cannot digest certain substances—all-important fiber, for example—microbes step up to perform chemistry no human can.

"But this kind of microbial metabolism can also be detrimental," said Maini Rekdal, a graduate student in the lab of Professor Emily Balskus and first-author on their new study published in Science. According to Maini Rekdal, gut microbes can chew up medications, too, often with hazardous side effects. "Maybe the drug is not going to reach its target in the body, maybe it's going to be toxic all of a sudden, maybe it's going to be less helpful," Maini Rekdal said.

In their study, Balskus, Maini Rekdal, and their collaborators at the University of California San Francisco, describe one of the first concrete examples of how the microbiome can interfere with a drug's intended path through the body. Focusing on levodopa (L-dopa), the primary treatment for Parkinson's disease, they identified which bacteria out of the trillions of species is responsible for degrading the drug and how to stop this microbial interference.

Parkinson's disease attacks nerve cells in the brain that produce dopamine, without which the body can suffer tremors, muscle rigidity, and problems with balance and coordination. L-dopa delivers dopamine to the brain to relieve symptoms. But only about 1 to 5% of the drug actually reaches the brain.

This number—and the drug's efficacy—varies widely from patient to patient. Since the introduction of L-dopa in the late 1960s, researchers have known that the body's enzymes (tools that perform necessary chemistry) can break down L-dopa in the gut, preventing the drug from reaching the brain. So, the pharmaceutical industry introduced a new drug, carbidopa, to block unwanted L-dopa metabolism. Taken together, the treatment seemed to work.

"Even so," Maini Rekdal said, "there's a lot of metabolism that's unexplained, and it's very variable between people." That variance is a problem: Not only is the drug less effective for some patients, but when L-dopa is transformed into dopamine outside the brain, the compound can cause side effects, including severe gastrointestinal distress and cardiac arrhythmias. If less of the drug reaches the brain, patients are often given more to manage their symptoms, potentially exacerbating these side effects.

Maini Rekdal suspected microbes might be behind the L-dopa disappearance. Since previous research showed that antibiotics improve a patient's response to L-dopa, scientists speculated that bacteria might be to blame. Still, no one identified which bacterial species might be culpable or how and why they eat the drug.

So, the Balskus team launched an investigation. The unusual chemistry—L-dopa to dopamine—was their first clue.

Few bacterial enzymes can perform this conversion. But, a good number bind to tyrosine—an amino acid similar to L-dopa. And one, from a food microbe often found in milk and pickles (Lactobacillus brevis), can accept both tyrosine and L-dopa.

Using the Human Microbiome Project as a reference, Maini Rekdal and his team hunted through bacterial DNA to identify which gut microbes had genes to encode a similar enzyme. Several fit their criteria; but only one strain, Enterococcus faecalis (E. faecalis), ate all the L-dopa, every time.

With this discovery, the team provided the first strong evidence connecting E. faecalis and the bacteria's enzyme (PLP-dependent tyrosine decarboxylase or TyrDC) to L-dopa metabolism.

And yet, a human enzyme can and does convert L-dopa to dopamine in the gut, the same reaction carbidopa is designed to stop. Then why, the team wondered, does the E. faecalis enzyme escape carbidopa's reach?

Even though the human and bacterial enzymes perform the exact same chemical reaction, the bacterial one looks just a little different. Maini Rekdal speculated that carbidopa may not be able to penetrate the microbial cells or the slight structural variance could prevent the drug from interacting with the bacterial enzyme. If true, other host-targeted treatments may be just as ineffective as carbidopa against similar microbial machinations.

But the cause may not matter. Balskus and her team already discovered a molecule capable of inhibiting the bacterial enzyme.

"The molecule turns off this unwanted bacterial metabolism without killing the bacteria; it's just targeting a non-essential enzyme," Maini Rekdal said. This and similar compounds could provide a starting place for the development of new drugs to improve L-dopa therapy for Parkinson's patients.

The team might have stopped there. But instead, they pushed further to unravel a second step in the microbial metabolism of L-dopa. After E. faecalis converts the drug into dopamine, a second organism converts dopamine into another compound, meta-tyramine.

To find this second organism, Maini Rekdal left behind his mother dough's microbial masses to experiment with a fecal sample. He subjected its diverse microbial community to a Darwinian game, feeding dopamine to hordes of microbes to see which prospered.

Eggerthella lenta won. These bacteria consume dopamine, producing meta-tyramine as a by-product. This kind of reaction is challenging, even for chemists. "There's no way to do it on the bench top," Maini Rekdal said, "and previously no enzymes were known that did this exact reaction."

The meta-tyramine by-product may contribute to some of the noxious L-dopa side effects; more research needs to be done. But, apart from the implications for Parkinson's patients, E. lenta's novel chemistry raises more questions: Why would bacteria adapt to use dopamine, which is typically associated with the brain? What else can gut microbes do? And does this chemistry impact our health?

"All of this suggests that gut microbes may contribute to the dramatic variability that is observed in side effects and efficacy between different patients taking L-dopa," Balskus said.

But this microbial interference may not be limited to L-dopa and Parkinson's disease. Their study could shepherd additional work to discover exactly who is in our gut, what they can do, and how they can impact our health, for better or worse.

More information: V. Maini Rekdal el al., "Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism," Science (2019). science.sciencemag.org/cgi/doi … 1126/science.aau6323

"Gut microbes metabolize Parkinson's disease drug," Science (2019). science.sciencemag.org/cgi/doi … 1126/science.aax8937

Journal information: Science 

Provided by Harvard University 

https://medicalxpress.com/news/2019-06-gut-microbes-medication.html