Lowering Iron Levels in Brain May Help Treat Parkinson’s, Trial in People with PKAN Says

deferiprone study

Binding to, or chelating, toxic levels of iron in the brain can slow the progression of a neurodegenerative disorder known as pantothenate kinase-associated neurodegeneration (PKAN), results from a Phase 3 trial show.

These findings may be relevant for other neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s and multiple sclerosis, which are also associated with high levels of iron in the brain, its researchers say.

The results, ”Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study,” were published in the journal The Lancet Neurology.

Iron is required for normal physiological functions; however, excessive levels can be toxic and abnormal high levels of iron are seen in several neurodegenerative diseases, from PKAN to Parkinson’s, Alzheimer’s, and MS.

Researchers conducted a Phase 3 trial (NCT01741532), called TIRCON, to evaluate the safety and efficacy of deferiprone in treating PKAN, a form of neurodegeneration that results in severe, involuntary muscle contractions (dystonia).

Deferiprone is an oral iron chelator approved to treat conditions linked with iron overload after blood transfusions in people with thalassemia, an inherited blood disorder characterized by lower levels of hemoglobin and fewer red blood cells.

The trial enrolled 88 patients with pantothenate kinase-associated neurodegeneration from four hospitals in Germany, Italy, England and the US. The participants, ages 4 and older, were randomized to deferiprone at 30 mg/kg a day (divided into two equal doses) or a placebo. Treatment was maintained for 18 months followed by an 18-month open-label extension phase, the TIRCON-Extension trial (NCT02174848).

Using magnetic resonance imaging (MRI) scans of the brain, researchers observed that treatment with deferiprone significantly lowered concentrations of iron in a specific part of the brain, called the globus pallidus, after 18 months compared to levels in the placebo group.

The globus pallidus is a region that is connect to several brain regions, and supports functions that include motivation, cognition and action.

These findings are in line with a previous Phase2/3 (NCT00943748) clinical trial’s results in Parkinson’s patients treated with deferiprone.

Treatment with deferiprone also decreased the number of PKAN patients who required other medications to control dystonia (11% compared to 21% in the placebo group). Slight, but not significant, improvements in disease progression with deferiprone treatment after 18 months were also seen compared to placebo. This was assessed using the Barry-Albright Dystonia (BAD) scale, which tests the severity of dystonia in eight different body regions.

This improvement appeared to be greater in a subset of later-onset patients with atypical pantothenate kinase-associated neurodegeneration, who had almost a 50% slower disease progression rate when treated with deferiprone compared to placebo. In placebo group patients who switched to deferiprone treatment in the TIRCON-extension trial, disease progression slowed by more than 60%.

Deferiprone appeared to be well-tolerated, with placebo and treatment groups reporting similar side effects. Anemia was the exception, as 21% of deferiprone treated patients reporting this side effect compared to no patients in the placebo group.

“The finding that brain iron can be markedly lowered by a chelator may have important implications also for age-associated neurodegenerative conditions such as Parkinson’s disease,” Thomas Klopstock, the Ludwig-Maximilians-University of Munich and the study’s first author, said in a news release.

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‘On Chip’ Blood-Brain Barrier Model Paves Way for Personalized Therapy, Study Suggests

BBB-chip Emulate

Using stem cells, researchers have recreated the complexity of the blood-brain barrier (BBB) — a critical protective brain structure — in a chip roughly the size of an AA battery.

This personalized BBB experimental model, which combines stem cell research with Emulate’s Organ-Chip technology, will allow scientists to better understand how the barrier works while also providing a novel way to investigate several human neurological diseases. By recreating true-to-life biology in a chip, researchers at  Cedars-Sinai can assess tailored strategies for people affected by progressive brain disorders, such as Parkinson’s disease.

The model was described in the study, “Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications,” published in the journal Cell Stem Cell.

The BBB is a semipermeable membrane, made of a complex network of blood vessels, that works as a natural filter that selects what reaches the brain. It blocks toxins and other foreign substances that are in the bloodstream from entering brain tissue, and potentially damaging it.

However, the BBB also can prevent “good” chemical agents from entering and targeting the brain, creating a major barrier for the efficient delivery of therapeutics that need to reach the brain and central nervous system to work.

Given the BBB’s complexities, transposing it represents an important step for the development and efficacy of therapies targeting neurological disorders, such as Parkinson’s and Huntington’s disease.

Indeed, some studies have suggested that several human neurodegenerative diseases, including Parkinson’s, are linked to defects in the BBB that may prevent healthy and necessary natural molecules from reaching the brain. That, in turn, supports the progression of the disease, this research suggests.

To date, it remains very difficult to study and fully understand how the BBB works, and to address the extent of its involvement in neurological diseases.

Cedars-Sinai researchers developed an “on chip” model of the BBB that specifically mimics the behavior of the barrier’s blood vessels and their interaction with brain cells.

The team used inducible pluripotent stem cells (iPSCs) derived from three healthy donors and one patient with Huntington’s disease to test their new experimental model. iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of any type of human cell needed for therapeutic purposes.

Using specific chemical stimulus, the researchers were able to transform iPSCs into mature BBB blood vessel cells or brain cells. The cells were then cultured on Emulate’s chip slide, which allowed a platform for cells to reconstitute the complex microenvironment of the brain and BBB.

The recreated BBB model was able to selectively allow the transport of some molecules from the BBB side across to the brain cells, confirming that it was working as as it naturally does in the body.

The model formed a functioning unit of a blood-brain barrier that mimicked what occurs in the body — including blocking the entry of certain drugs.

Researchers then created a model derived from cells from Huntington’s patients and people with Allan-Herndon-Dudley syndrome, a rare congenital neurological disorder. That barrier showed a different permeability pattern compared with the BBB model derived from healthy volunteers.

“Altogether, these results suggest that patient-specific iPSC-based BBB-Chips may be used to predict inter-patient variability in BBB functions,” the researcher said. They said the models also may help “predict human central nervous system drug penetrability.”

This BBB-chip model paves the way for a promising avenue for precision medicine, the investigators said.

“The possibility of using a patient-specific, multicellular model of a blood-brain barrier on a chip represents a new standard for developing predictive, personalized medicine,” Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, and the study’s senior author, said in a press release.

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Man-made DNA Molecules May Help Prevent Parkinson’s, Study Finds

man made DNA molecules

Osaka University scientists have built short fragments of DNA that can stop the production of abnormal alpha-synuclein protein in the brain — which may advance the development of new therapies for the control and prevention of Parkinson’s disease.

The study, “Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease,” was published in Scientific Reports.

“Although there are drugs that treat the symptoms associated with PD [Parkinson’s disease], there is no fundamental treatment to control the onset and progression of the disease,” Takuya Uehara, PhD, the study’s lead author, said in a press release.

It is believed that gene therapy could someday be used to treat or halt Parkinson’s. Potential therapeutic targets include genes associated with the disorder, such as the SNCA gene — the gene that codes for the alpha-synuclein protein. Mutations in SNCA lead to the production and accumulation of an abnormal, and harmful, form of the alpha-synuclein protein within brain cells of people with Parkinson’s. As the disease progresses, neuronal toxic protein buildup increases, eventually leading to cellular death. That, in turn, leads to the onset of disease-related motor and non-motor symptoms.

“The antisense oligonucleotide (ASO) is a potential gene therapy for targeting the SNCA gene. ASO-based therapies have already been approved for neuromuscular diseases including spinal muscular atrophy (SMA) [Spinraza] and Duchenne muscular dystrophy [Exondys 51],” the researchers said.

Japanese researchers now looked for ways to prevent the production of toxic alpha-synuclein, hoping to eliminate Parkinson’s molecular trigger. To do so, they designed 50 small fragments of DNA that mirrored parts of  the coding sequence of the SNCA gene messenger RNA (mRNA).

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced: DNA is first transformed into mRNA, and eventually, into a protein.

The man-made DNA fragments, also known as amido-bridged nucleic acid-modified antisense oligonucleotides (AmNA-ASO), were stabilized with resilient cyclic amide structures (hence the term “amido-bridged”). Amide are compounds that confer structural rigidity.

In total, these 50 molecules covered around 80.7% of SNCA’s mRNA. In doing so, engineered molecules were able to bind to their matching natural mRNA sequence, disabling it from being translated into a protein.

Using human embryonic kidney cells that naturally produce alpha-synuclein, scientists observed that several of these engineered molecules reduced SNCA mRNA levels. One of the constructs, specifically number 19, significantly decreased SNCA mRNA levels to 24.5% of the normal alpha-synuclein levels, “suggesting that AmNA-ASO [number] 19 is highly potent for targeting SNCA mRNA in human cultured cells,” the researchers said.

Importantly, this particular ASO was efficiently delivered into the brains of mice using an intracerebroventricular (a fluid-filled interconnected brain cavity) injection, without the aid of additional chemical carriers. The ASO was then mainly taken up by neurons and neuronal support cells.

Further testing, using a Parkinson’s mouse model that had disease-characteristic motor impairment, revealed AmNA-ASO number 19 successfully reduced alpha-synuclein protein levels, and significantly eased symptom severity 27 days after administration.

The researchers concluded that reducing alpha-synuclein mRNA and corresponding protein levels via gene therapy seems to enhance Parkinson’s-related motor manifestations in mice. This highlighted AmNA-ASO’s potential as a novel therapy for this neurodegenerative disorder.

The ASO Spinraza (nusinersen) was approved by the U.S. Food and Drug Administration (FDA) in December 2016 for treating spinal muscular atrophy. The FDA granted accelerated approval to Exondys 51 (eteplirsen) in September 2016, making it the first drug approved to treat Duchenne muscular dystrophy.

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In Addition to a Cure for Parkinson’s, What Else Do We Really Want?


We all want something in life. We want to win the lottery or find our perfect mate. For those of us with a chronic illness, we’d be more than satisfied with a cure for our disease. 

Until we find a cure for Parkinsons’s disease, I’ve compiled a list of things that might help people with the disease to live with greater ease:

1. Some Parkinson’s patients would do anything to regain their sense of smell. It is a brighter day when we get a whiff of a rose’s fragrance or the aroma of garlic bread.

2. We want to feel good. I’m not merely referring to the absence of nausea, although that comes into play with all of the medications that can make us feel sick. We also want to feel positive about ourselves despite this disease taking so much from us.

3. We often feel that we have nothing left to offer, and we would like someone to remind us that we still have a purpose despite Parkinson’s.

4. I’ve heard of people with Parkinson’s whose family members or friends believed they were pretending to have the disease. Here’s what I say to them: “Don’t you think we have better things to do with our time than pretend to have an incurable disease?”

5. We want others to understand that although some of our symptoms can be hard to see, the disease is real. Our tremors, pain, lack of balance, and risk of falls are genuine.

6. Parkinson’s disease can be summed up as a loss of dopamine in the brain.

7. Our constant companion is this little monster, but we would like a reprieve from frequent shaking.

8. It would be fantastic if others were aware of the struggles and invisible symptoms that we live with so that they can fully understand the urgency of a cure.

9. It is common for people with Parkinson’s to experience sleepiness as a symptom and as a medication side effect. As a result, we can spend a good deal of our day sleeping. We also struggle to get a good night’s sleep. It can be a vicious cycle. We would love a treatment that doesn’t knock us out for half of the day but instead knocks out Parkinson’s.

10. Besides having a little plastic bat to bonk others over the head when they make thoughtless comments such as, “You don’t look like you have Parkinson’s disease,” a cure would also be welcome!


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.

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At $52B Per Year, Economic Burden of Parkinson’s in U.S. Double Previous Estimates, Study Reports

economic burden Parkinson's

The annual economic burden of Parkinson’s disease on U.S. patients, families, and the federal government is nearly $52 billion, more than double the previous estimates, according to a comprehensive study by the Michael J. Fox Foundation (MJFF).

This is the first study to examine the various ways Parkinson’s affects a patient’s finances and their ability to participate in the labor market, according to a press release. The report is touted as the most complete assessment to date of the disease’s economic toll.

The $51.9 billion includes some $25.4 billion that goes toward hospitalizations, medications, and other direct medical costs, and $26.5 billion in non-medical costs such as missed work, lost wages, early forced retirement, and family caregiver time.

Previously, the combined direct and indirect costs of Parkinson’s in the United States were estimated at $25 billion annually. For many years, according to the release, the disorder’s financial impact was vastly underestimated.

Called “The Economic Burden of Parkinson’s Disease,” the study was conducted with support from the Parkinson’s Foundation, American Parkinson Disease Association, The Parkinson Alliance, and several pharmaceutical companies.

“There are a lot of surprise costs when you have Parkinson’s,” said Steve DeWitte, a Parkinson’s research funding advocate. “Beyond the rising costs of medications and healthcare, my family has shouldered the financial burden of my having to leave the workforce 15 years earlier than I had planned. That means our income dropped by more than half, and we’ve had to figure out how to stretch our budget to cover the everyday household tasks I can no longer physically do.”

The study also found that the federal government spends nearly $25 billion each year on patient care. Of that, $2 billion is paid through social security, with the balance handled by Medicare. Roughly 90% of Parkinson’s patients receives Medicare benefits.

“This data will help facilitate a new level of outcome-driven conversations with members of Congress who oversee federal programs that affect the lives of the 1 million people with Parkinson’s in the United States,” said Todd Sherer, PhD, MJFF’s CEO. “Investing more in research toward better treatments and a cure will ultimately relieve the burden on already-strained programs like Medicare, Medicaid and Social Security.”

These findings underscore the prospective impact of policy or treatment interventions, he added. Advocates now have more specific data they can use to educate lawmakers and to urge them to prioritize biomedical research investment and to develop support initiatives.

To understand and examine the cost components of Parkinson’s disease, the researchers used data from Medicare, the Centers for Disease Control and Prevention, the U.S. Census Bureau, and other sources. Such data-driven knowledge is expected to go a long way toward raising funds for research to find therapies to ultimately ease the growing burden.

“These results provide deep insight into the indirect costs — those costs the people living with Parkinson’s and their families must shoulder alone,” said James Beck, PhD, the Parkinson’s Foundation’s senior vice president and chief scientific officer. “Knowing this information will allow us to better serve people with Parkinson’s and their families in the areas they’re most concerned about and where we can have the most impact.”

The MJFF is now examining how this study can help shape its research policy priorities, as well as future public policy efforts related to the economic burden of Parkinson’s. For one, it plans to develop a project model to assess how specific actions — such as a ban on chemicals associated with Parkinson’s or federal approval of a disease-modifying treatment — would affect the economic burden.

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The Link Between Compassionate Support and Wellness

PD Dr. C's Journey, loss of vision

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.

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

Midbrain area measurements

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.

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MJFF Assists Nitrome Biosciences’ Pursuit of Parkinson’s Therapies

Nitrome Bioscience

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.

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

anle138b molecule

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 symptoms associated 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.

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

HYPE protein

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.”

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