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Specific Dopamine-producing Neurons Crucial to Adaptive Movement, Early Study Finds

motor skills and Parkinson's

Dopaminergic neurons — nerve cells gradually lost to Parkinson’s progression — that contain an enzyme called aldehyde dehydrogenase 1A1 are essential for acquiring the motor skills needed for proper movement in given situations, a mouse study reports.

The research, “Distinct connectivity and functionality of aldehyde dehydrogenase 1A1-positive nigrostriatal dopaminergic neurons in motor learning,” was published in Cell Reports. The work was developed by the Intramural Research Program of the National Institute on Aging (IRP-NIA).

Parkinson’s disease severely affects dopaminergic neurons, those that produce dopamine, a neurotransmitter (cell-signaling molecule) that relays information between nerve cells and between the brain and the rest of the body.  These neurons are found in two specific brain regions involved in motor control: the striatum and the substantia nigra.

Nerve cells may or not contain aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that is involved in cellular detoxification. Parkinson’s seems to mostly damage ALDH1A1-positive dopaminergic neurons, suggesting the enzyme may be a key player in this neurodegenerative disorder.

Both ALDH1A1-positive and ALDH1A1-negative dopaminergic nerve cells contribute to voluntary motor behavior. But the degree to which ALDH1A1-positive neurons are crucial to acquiring motor skills remains to be understood.

Using a mouse model of Parkinson’s, scientists targeted  dopaminergic neurons positive for ALDH1A1, and produced a detailed connectivity map of these specific neuronal networks in the mouse brain.

ALDH1A1-positive neurons were found to be in constant communication with other brain structures there. Importantly, researchers found that those dopamine-producing neurons of the striatum and substantia nigra that received the greatest percentage of molecular information (input) were located in the caudate-putamen nuclei, a brain region involved in movement control.

Researchers then selectively removed ALDH1A1-positive neurons to mimic the degeneration pattern observed in late-stage Parkinson’s disease. The animals’ ability to show new motor skills — new ways of voluntary movement, like foot position for maintaining balance while walking on a moving surface — was assessed using the rotarod test. In this test, mice must learn to balance while walking on a constantly rotating rod much like a treadmill.

Mice without ALDH1A1-positive neurons displayed a distinctly poorer ability to learn new motor skills, and slower walking speeds compared to control animals.

“Compared with a modest reduction in high-speed walking, the ALDH1A1+ nDAN-ablated mice showed a more severe impairment in rotarod motor skill leaning,” the researchers wrote. “Unlike control animals … [these] mice essentially failed to improve their performance during the course of rotarod tests.” (nDANs are nigrostriatal dopaminergic neurons.)

These animals were then treated with dopamine replacement therapy, either levodopa or a dopamine receptor agonist, one hour before a new motor skills assessment. Dopamine replacement therapy is standard treatment for the motor symptoms associated with Parkinson’s.

Levodopa (L-DOPA) treatment allowed the animals without ALDH1A1-positive neurons to travel longer distances, and to walk more frequently at higher speeds during a session. But it failed to improve their ability to acquire new motor skills during repeated tests. Treatment with a dopamine receptor agonist was also ineffective.

“When the ALDH1A1+ nDANs were ablated after the mice had reached maximal performance, the ablation no longer affected the test results, supporting an essential function of ALDH1A1+ nDANs in the acquisition of skilled movements. These findings are in line with the theory that nigrostriatal dopamine serves as the key feedback cue for reinforcement learning,” the researchers wrote.

These results provide “a comprehensive whole-brain connectivity map,” they concluded, and reveal a key role of ALDH1A1-positive neurons in newly learned motor skills, suggesting that motor learning processes require these neurons to receive a multitude of information from other nerve cells and to supply dopamine with “dynamic precision.”

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Early Involvement of Caudate Brain Region Linked to Worse Prognosis in Parkinson’s Patients, Study Finds

caudate involvement

Almost half of people in the early stages of Parkinson’s disease already have signs of neurodegeneration in a brain region called the caudate, which was previously thought to affect mostly those at advanced disease stages, a study reports.

Early caudate involvement on both sides of the brain, as seen by DaTscan imaging of the brain, appeared to predict the risk for worse outcomes, including cognitive impairment, depression, and gait problems, over a four-year follow-up period.

These findings suggest that caudate involvement detected through DaTscan neuroimaging may serve as an early biomarker to identify patients at a greater risk of faster disease progression in the near future.

The study, “Clinical implications of early caudate dysfunction in Parkinson’s disease,” was published in the Journal of Neurology, Neurosurgery & Psychiatry.

Parkinson’s disease is believed to be caused by the impairment or death of dopamine-producing nerve cells (neurons) in a region of the brain called the substantia nigra, which controls the body’s balance and movement.

When the disease is established, or advanced, the degeneration of dopaminergic neurons and nerve fibers frequently extends to a brain region called the caudate nucleus. This region plays important roles in motor control as well as in various other non-motor tasks, such as learning and sleep.

In fact, the loss of dopaminergic function in this region is known to contribute to the hallmark symptoms of Parkinson’s including cognitive impairment, depression, sleep disorders, and gait problems.

Although less common, caudate dopaminergic dysfunction may also emerge in the early stages of the disease, in which case it could also contribute to the onset of non-motor symptoms. However, the frequency of this specific brain impairment in early Parkinson’s is unknown as are its clinical implications for patients.

To address this lack of knowledge, a team, led by researchers at the University of Milan in Italy and Newcastle University in England, investigated the prevalence of caudate dopaminergic dysfunction in people who were still in the very early stages of Parkinson’s.

By comparing the participants’ state at the beginning of the study and four years later, they also looked for associations between caudate involvement and an increased risk of disease progression.

They analyzed clinical data from 397 patients who had had a Parkinson’s diagnosis for two years or less, and were participating in the Parkinson’s Progression Markers Initiative (PPMI), an ongoing study attempting to identify biomarkers of disease progression. The team compared the collected clinical data from Parkinson’s patients with that of 177 healthy volunteers.

Caudate dysfunction was detected using 123I-FP-CIT single-photon emission computed tomography, commonly known as DaTscan. This is an imaging technique that depicts the levels of dopamine transporters in the brain that is often used to confirm a Parkinson’s diagnosis.

Based on DaTscan imaging data, the participants were divided into three groups: those who had no reduction of dopamine transporters, those who showed reduction in just one side of the brain, and those who had involvement of both sides of the brain.

Initial data showed that 51.6% of the patients had signs of normal caudate dopamine function, while 26% had caudate dopaminergic dysfunction on one side of the brain (unilateral), and 22.4% on both sides (bilateral).

Four years later, the patients who initially had bilateral caudate involvement were found to experience more frequent and worse cognitive impairment and depression, and more severe gait disability.

In general, after four years of follow-up, more patients showed a loss of dopaminergic nerve fibers in the caudate, compared with the study start, affecting 83.9% of patients (unilateral 22.5%, bilateral 61.4%).

“In this study, we have demonstrated a high frequency of early caudate dopaminergic dysfunction in patients with recently diagnosed [Parkinson’s disease],” the researchers wrote.

“Our study suggests that early bilateral caudate dopaminergic dysfunction is associated with an increased frequency of clinically significant depression and to worse depressive symptoms, regardless of age,” they added.

DaTscan parameters used to define the presence of early caudate dysfunction may be a “valid indicator of more rapid onset of such symptoms,” they said, which may help in “identifying patients at risk of clinical progression to cognitive impairment, depression, and gait problems in the near future.”

Assessment of caudate dopaminergic denervation may also assist clinicians in better predicting disease course at an early stage and identifying patients who may benefit the most from early, targeted disease-modifying therapies.

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GDNF Shows Potential as Neurorestorative Treatment for Parkinson’s

GDNF studied

Infusion of a naturally occurring protein, GDNF, into a motor control area of the brain may restore cells damaged by Parkinson’s disease and ease patients’ symptoms, results from a European clinical trial suggest.

The study, “Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease” was published in the Journal of Parkinson’s Disease.

Evidence shows that glial cell line-derived neurotrophic factor (GDNF) supports the growth, survival, and differentiation of dopaminergic neurons — those that produce dopamine and progressively degenerate in Parkinson’s disease. In animal models of Parkinson’s, GDNF has consistently demonstrated both neuroprotective and neurodegenerative effects when provided continuously.

Researchers developed a three-part clinical trial (EudraCT Number: 2013-001881-40) to study the safety and effectiveness of GDNF infusions in Parkinson’s patients. The trial first recruited six patients to assess the safety of the treatment. Then, 35 more participants entered the nine-month, double blind trial in which half were given monthly infusions of GDNF. The other half received placebo infusions through an implant that delivered the treatment directly to the brain through a port placed behind the ear.

This part of the study showed that patients who received monthly doses of GDNF into their putamen — a brain region involved in movement control that’s deeply damaged in Parkinson’s — had a significant increase of dopamine levels in the brain compared to the placebo group. However, the apparent increase in dopamine levels were not reflected on patients’ clinical status.

“The spatial and relative magnitude of the improvement in the brain scans is beyond anything seen previously in trials of surgically delivered growth-factor treatments for Parkinson’s,” principal investigator Alan L. Whone, PhD, said in a press release. Whone is in Translational Health Sciences, Bristol Medical School, University of Bristol, and Neurological and Musculoskeletal Sciences Division, North Bristol NHS Trust, Bristol, UK,  “This represents some of the most compelling evidence yet that we may have a means to possibly reawaken and restore the dopamine brain cells that are gradually destroyed in Parkinson’s,” he said.

Using the same patient sample (41 subjects, ages 35–75) researchers further assessed the effects of continued (21 patients who had received GDNF) or new (20 patients who had received placebo) exposure to GDNF for another nine months in the open-label extension phase of the trial. Dosing followed the same protocol as before with GDNF infusion given every month.

Although all patients knew they were receiving GDNF, they remained oblivious to what their treatment in the previous study was.

The primary goal of the study was measure the percentage change from parent trial week zero to week 80 (or week 40, depending on the study group) in the “off” state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. As disease progresses, patients experience off periods more frequently. Such episodes are characterized by the reappearance or worsening of symptoms due to diminishing effects of levodopa therapy.

The treatment had no treatment-emergent safety issues, but all patients experienced at least one adverse side effect, including application site infection, headache, back pain, and uncontrollable muscle contraction (dystonia).

By 18 months (all participants had received GDNF), both groups showed a trend toward score reduction, indicating motor function improvement. GDNF also was found safe when administered over this length of time. However, there were no significant differences in off state UPDRS motor score between patients who received GDNF for 18 months and those who received it for nine months only (parent study placebo group).

Importantly, total off time and good-quality “on” time per day improved in both study groups.

In comparison to the beginning of the parent trial, mean total off time per day decreased by an average of 1.5 hours in patients who received GDNF throughout the whole study, and by 0.8 hours in the those who received placebo and GDNF. “Good-quality ON time increased by [an average of 1.6] hours in the GDNF/GDNF group and by [0.5] hours in the placebo/GDNF group,” researchers wrote.

“This trial has shown that we can safely and repeatedly infuse drugs directly into patients’ brains over months or years. This is a significant breakthrough in our ability to treat neurological conditions, such as Parkinson’s, because most drugs that might work cannot cross from the blood stream into the brain due to a natural protective barrier,” said senior author Steven Gill, honorary professor in neurosurgery at the University of Bristol, and designer of the GDNF delivery system (Convection Enhanced Delivery, CED).

“I believe that this approach could be the first neurorestorative treatment for people living with Parkinson’s, which is, of course, an extremely exciting prospect,” Gill stated.

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Abnormal Brain Cell Type Leads to Parkinson’s-Related Neurodegeneration, Study Contends

brainstem cells

Scientists have found that an abnormal version of brain cells called astrocytes contribute to the accumulation of alpha-synuclein protein, the main component of Parkinson’s disease hallmark Lewy bodies.

Their study, “Patient-specific iPSC-derived astrocytes contribute to non-cell autonomous neurodegeneration in Parkinson’s disease,” was published in Stem Cell Reports.

Parkinson’s disease is linked to degeneration of the ventral midbrain (relating to the inferior part of the brain), a region that houses dopamine-releasing neurons.

Post-mortem analysis of Parkinson’s disease brain tissue has revealed astrocytes accumulate toxic amounts of alpha-synuclein during the disease process. Research also suggests that this toxic protein can be taken up and spread from astrocytes to neurons, causing neuronal death.

Astrocytes are star-shaped cells that outnumber neurons by fivefold. Found in the central nervous system, astrocytes are known as housekeeping cells because they care for neurons, nurture them and “clean up” after them.

Investigators set up to further investigate a role for Parkinson’s disease-related astrocyte dysfunction in midbrain nerve cell death.

They generated astrocytes and ventral midbrain dopaminergic neurons from induced pluripotent stem cells (iPSCs) of healthy individuals and of patients with the LRRK2 G2019S mutation, the most commonly found mutation in Parkinson’s disease.

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 almost any type of human cell needed.

Although LRRK2’s main function is not known, it seems to play a key role in mitochondria — cells’ powerhouses — namely in autophagy, a process that allows cells to break down and rebuild their damaged components.

Healthy neurons and Parkinson’s astrocytes were together in the same lab dish to study their cellular interactions. Results revealed a significant decrease in the number of healthy ventral midbrain dopaminergic neurons when cultured together with Parkinson’s disease astrocytes, which was associated with astrocyte-derived alpha-synuclein aggregation.

Healthy neuronal death was caused by the shortening and disintegration of the cells’ projecting branches, known as axons and dendrites.

When healthy astrocytes were cultured with Parkinson’s neurons, the housekeeping cells partially prevented the appearance of disease-related cellular changes and alpha-synuclein buildup in the diseased neurons.

“We found Parkinson’s disease astrocytes to have fragmented mitochondria, as well as several disrupted cellular degradation pathways, leading to the accumulation of alpha-synuclein,” the study’s co-first author Angelique di Domenico, PhD, said in a press release.

Because Parkinson’s astrocytes had high levels of alpha-synuclein in them, researchers hypothesized that the toxic protein could be transferred to healthy dopamine-producing neurons and cause the damage they had previously observed.

Using the CRISPR-Cas9 gene editing tool, the team generated two new astrocyte lines (representing one Parkinson’s patient and one healthy control). This allowed them to “tag” alpha-synuclein within living cells and track the protein as it was generated by astrocytes and transferred to dopamine-producing neurons.

As expected, alpha-synuclein in Parkinson’s astrocytes accumulated at abnormally high levels and, upon culture with healthy dopamine-producing neurons, a direct transfer of astrocytic alpha-synuclein to neurons was observed.

Researchers then used this gene-editing technology to generate Parkinson’s astrocytes that lacked the LRRK2 G2019S mutation. Abnormal alpha-synuclein accumulation did not occur in gene-corrected astrocytes and upon culture with healthy neurons, there was no accumulation of alpha-synuclein or decrease in neuron survival.

Researchers then treated Parkinson’s astrocytes with a chemical designed to correct the cells’ disrupted clean-up system.

“We were elated to see after treatment that the cellular degradation processes were restored and alpha-synuclein was completely cleared from the Parkinson’s disease astrocytes,” di Domenico said. “These results pave the way to new therapeutic strategies that block pathogenic interactions between neurons and glial cells.”

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Engineered Stem Cells Could Be Next Parkinson’s Treatment, Researchers Say

gene editing

Cutting out a portion of or removing a gene linked to Parkinson’s disease protects against the formation of toxic protein clumps within brain cells, scientists have found.

This discovery has the potential to significantly affect the development of next-generation cell-based therapies, which involve injecting healthy cells into brain regions already affected by the disease. Researchers believe the approach may help relieve motor symptoms such as tremor and balance issues.

Findings were published in the study, “Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene,” in the European Journal of Neuroscience. The work was funded by the U.K. Centre for Mammalian Synthetic Biology, UCB, and The Cure Parkinson’s Trust.

Mutations in the SNCA gene have been found to cause Parkinson’s, a condition characterized by the selective death of midbrain dopamine-producing neurons due to clustering of a protein called alpha-synuclein, also known as Lewy bodies.

Transplantation of dopamine-producing neurons has proved useful in disease management because it can reinnervate Parkinson’s-affected brain regions, restore dopamine levels, and provide symptom relief.

Clinical studies on the transplant of fetal mesencephalic (meaning “of or relating to the midbrain”) tissue into the striatum — a critical area of the brain involved in Parkinson’s — have shown that although some patients saw their motor symptoms improved, others had transplant-induced dyskinesias — abnormal, uncontrolled, and involuntary movement.

Importantly, transplanted tissue (grafts) older than 10 years developed Lewy bodies, which reduced the symptomatic benefit to the patient.

“These clinical observations highlight the need for cell therapies that are resistant to the formation of Lewy bodies. … Such disease-resistant cells will be particularly important for patients with young-onset Parkinson’s or genetic forms of the condition with substantial alpha-synuclein burden,” the researchers wrote.

The team used a gene editing tool known as CRISPR-Cas9. This technique allows scientists to edit parts of the genome by removing, adding, or altering specific sections of the DNA sequence.

Using stem cells, researchers created two distinct cell lines: one with snipped-out portions of the SNCA gene and another without the SNCA gene.

These stem cells were then transformed into dopamine-producing neurons and treated with a chemical agent (recombinant alpha-synuclein pre-formed fibrils) to induce the formation of Parkinson’s-related Lewy bodies.

The team reported that wild-type neurons, or unedited brain cells, were fully susceptible to the formation of toxic aggregates, while engineered cells were significantly resistant to Lewy body formation.

“We know that Parkinson’s disease spreads from neuron [to] neuron, invading healthy cells. This could essentially put a shelf life on the potential of cell replacement therapy. Our exciting discovery has the potential to considerably improve these emerging treatments,” Tilo Kunath, PhD, group leader at the Medical Research Council’s Centre for Regenerative Medicine, University of Edinburgh, and senior author of the study, said in a press release.

By finding a way to “shield” cells from Parkinson’s molecular changes, scientists may have opened the door to the development of cell therapies capable of diverting time’s negative effect on transplanted tissue.

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Plant Compound, Arbutin, Eases Some Symptoms in Parkinson’s Mouse Model, Study Shows

arbutin plant compound

Arbutin, a natural compound found in plants such as bearberry leaves and pear trees, was able to protect dopaminergic neurons and reduce behavioral deficits and oxidative stress in an animal model of Parkinson’s disease, a study reports.

The study, “Arbutin attenuates behavioral impairment and oxidative stress in an animal model of Parkinson’s disease,” was published in the Avicenna Journal of Phytomedicine.

Parkinson’s disease is characterized by the progressive deterioration and death of a specific subset of brain cells called dopaminergic neurons. The loss of these nerve cells causes the disease’s neurological symptoms such as tremors, muscle rigidity, slow movements, and postural instability.

However, the molecular mechanisms by which these dopaminergic neurons are selectively affected and degenerate over time remains unknown.

Increasing evidence shows that oxidative stress is an important factor that contributes to disease progression.

Oxidative stress is caused by an imbalance between the body’s production of potentially harmful reactive oxygen species and the ability of cells to detoxify them. These reactive oxygen species can damage crucial molecules in cells including DNA and proteins, hampering their function and ultimately their ability to survive.

Current treatment options for Parkinson’s are still limited, losing effectiveness over time and often associated with side effects including nausea, fatigue, fainting, and increased tremors. Therefore, new therapeutics are urgently needed.

In this study, researchers investigated the effectiveness of a new compound — arbutin — in the treatment of Parkinson’s disease. Arbutin is naturally found in various plants, such as bearberry leaves and pear trees.

The team used a mouse model that mimics the symptoms and molecular alterations of the human disease. Mice were injected with 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), known for inducing Parkinson’s symptoms similar to those observed in human patients.

Animals were divided into three groups — a control group injected with a saline (innocuous) solution; a second group treated with a saline solution for seven days, followed by MPTP, injected into the abdomen; and a third group receiving arbutin (50 mg/kg) injected into the abdomen, before receiving MPTP injections.

On the 14th day of the experiment, researchers evaluated behavioral deficits using a locomotion test, hanging wire test, and forepaw stride length. They also analyzed the animals’ blood and brain tissue.

Arbutin-treated animals improved their locomotor activity and increased their forepaw step distance over the controls. Treated animals were also able to hand upside down (hanging wire test) for longer periods of time than the controls.

Arbutin also reduced blood and brain levels of specific molecules associated with oxidative stress, such as nitric oxide, previously shown to promote the death of dopaminergic neurons. The expression of thiobarbituric acid reactive substance (TBARS), a marker of oxidative stress whose levels were reported to be higher in the brains of Parkinson’s patients, was also reduced, both in the brain and blood of arbutin-treated animals.

These findings suggest that “arbutin can effectively attenuate behavioral deficits and reduce oxidative and nitrosative stress in MPTP- induced PD [Parkinson’s] model,” the researchers wrote.

They are now interested in clarifying “the exact molecular mechanisms by which arbutin can protect dopaminergic neurons.”

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Deterioration of Nerve Cell Structure Not the Main Cause of Early Parkinson’s Symptoms, Mouse Study Suggests

neuron structure changes

Although the structure of dopaminergic neurons gradually deteriorates before cell death, these alterations do not seem to account for the subtle impairments seen during the early stages of Parkinson’s disease, a mouse study has found.

The study, “Progressively Disrupted Somatodendritic Morphology in Dopamine Neurons in a Mouse Parkinson’s Model,” was published in Movement Disorders.

Parkinson’s is a progressive neurodegenerative disorder caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control.

Previous studies in animal models have shown that neuron dysfunction and cell death start to occur before animals display noticeable motor symptoms associated with Parkinson’s. However, the precise morphological (structural) and functional changes that occur in neurons at this early stage of disease are still not very well understood.

Researchers from the University of Texas Health used a mouse model of adult-onset parkinsonism that perfectly mirrors “the slow, progressive course of Parkinson’s seen in the majority of patients,” according to the study.

These mice, called MitoPark, lack the mitochondrial transcription factor A (TFAM) gene specifically in dopaminergic neurons. As a result, at 12 weeks of age, they show a marked decrease of brain innervation in the striatum — a region responsible for motor coordination — followed by neuron cell death at 30 weeks old.

To analyze the morphology of individual neurons in brain slices from MitoPark mice during the early stages of disease, researchers used a technique called whole-cell patch clamp — a technique that allows the study of the electrical properties of neurons — together with fluorescent labeling.

At 16 weeks of age, these animals’ dopaminergic neurons were significantly reduced in size with a lower number of branching points in dendrites — the long, slender projections of a neuron that carry an electrical signal from the cell body to the point of contact with another neuron, called the synapse.

“Alterations in somatic [cell body] and dendritic structure are likely to have direct effects on dopamine-dependent motor function and reward learning. In these neurons, dendrites serve important roles as sites for synaptic termination and contribute to many determinants of cell excitability,” the researchers said.

These defects worsened significantly as animals got older, from 16 to 31 weeks of age, eventually leading to neuronal death.

“Dendritic branching and soma size, although intact in dopamine neurons from 12-week-old MitoPark mice, are progressively and severely disrupted in a manner that undoubtedly impairs cellular function in advance of neuronal death,” the researchers wrote.

Although this decline in neuron morphology occurred at a similar rate in animals from both sexes, it did not begin until after the age at which the first mild locomotor and learning alterations start to occur (approximately 12 weeks).

As a result, the progressive and severe decline in neuronal morphology that occurs prior to cell death does not seem to be involved in the initial motor and cognitive impairments observed in this mouse model.

“This work could help identify the ideal time window for specific treatments to halt disease progression and avert debilitating motor deficits in Parkinson’s patients,” the researchers concluded.

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Astilbin, Found in Plants, Protects Neurons and Improves Motor Control, Mouse Study Finds

astilbin study

A compound found in various types of plants, called astilbin, can protect neurons by preventing over-activation of glia cells (nerve cells that support neurons), excessive alpha-synuclein production, and oxidative stress, researchers working in a mouse model of Parkinson’s disease report.

Their study, “Neuroprotective effects of Astilbin on MPTP-induced Parkinson’s disease mice: Glial reaction, α-synuclein expression and oxidative stress,” was published in International Immunopharmacology.

Parkinson’s disease is mainly caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control.

The disease also seems to be associated with over-production of the protein alpha-synuclein in nerve cells of the brain. When this protein clumps together, it gives rise to small toxic deposits inside brain cells, inflicting damage and eventually killing them.

Parkinson’s characteristic symptoms are related to the resulting loss of dopamine-producing nerve cells, and its therapies typically focus on restoring dopamine signaling in the brain to ease problems with movement and balance.

Astilbin, a flavanonol also found in alcoholic beverages (it’s a constituent of wine grape), is known to possess anti-inflammatory, anti-oxidant, and neuroprotective properties.

For this reason, a team of Chinese researchers tested whether astilbin could protect neurons from damage in mice chemically induced to develop Parkinson’s disease.

Researchers injected animals with MPTP — a neurotoxin that has been shown to trigger Parkinson’s symptoms in mice and non-human primates — once a day for five days. Once the animals showed classic Parkinson’s symptoms of motor impairment, they were treated with either astilbin or a saline solution (as a control group) for another seven days.

Behavioral tests revealed that mice given astilbin showed a remarkable improvement in motor function compared to control animals, with significant differences seen in movement scores on a pole and traction test between treated and untreated diseased mice.

Biochemical and molecular analysis also showed that astilbin blocked the drop in dopamine brain levels that’s associated with MPTP treatment, minimized the loss of dopaminergic neurons and the activation of glia cells in the substantia nigra, prevented over-production of alpha-synuclein, and reduced oxidative stress — the cellular damage that occurs as a consequence of high levels of oxidant molecules.

Moreover, researchers reported that astilbin activated PI3K/Akt signaling — a chemical cascade involved in the survival and growth of dopaminergic neurons — in the brain after MPTP administration. This finding suggests, they wrote, “that treatment with AST [astilbin] prevents the loss of dopaminergic neurons in MPTP-induced PD [Parkinson’s disease] mice by inducing the activation of the PI3K/Akt signaling pathway.”

Astilbin “exerts neuroprotective effects” on the diseased mice “by suppressing gliosis [activation of glia cells], α-synuclein overexpression and oxidative stress, suggesting that AST could serve as a therapeutic drug to ameliorate PD,” the researchers concluded.

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Inflammation-related Protein Complex a Potential Therapy Target for Parkinson’s, Study Says

protein complex

Oral administration of a small molecule specifically blocked the activation of a stress-sensing protein complex called the NLRP3 inflammasome and prevented the loss of brain cells, resulting in significantly improved motor function in a mouse model of Parkinson’s disease, a study reports.

Findings also revealed that the inflammasome is activated in Parkinson’s patients.

“We have used this discovery to develop improved drug candidates and hope to carry out human clinical trials in 2020,” Trent Woodruff, PhD, the study’s senior author, said in a press release.

The study, “Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice,” appeared in the journal Science Translational Medicine.

Parkinson’s is characterized by the progressive loss of dopamine-producing neurons in an area of the brain called the substantia nigra, leading to the characteristic motor symptoms. Dysfunction of the mitochondria, which provide energy to cells, accumulation of protein clumps primarily containing fibrils of alpha-synuclein, and neuroinflammation are other well-known alterations occurring in the brains of Parkinson’s patients.

The inflammasome is a multiprotein complex responsible for the activation of inflammatory responses that works as a sensor of environmental and cellular stress. Work in Alzheimer’s disease has shown that the accumulation of protein clumps can activate inflammasomes, driving inflammation in the central nervous system (CNS), which consists of the brain and spinal cord.

Using postmortem brains from Parkinson’s patients and mouse models of the disease, researchers from The University of Queensland in Australia showed that both fibrils of alpha-synuclein and loss of dopamine-producing neurons triggered the activation of the NLRP3 inflammasome in microglia — a type of cell that plays a crucial role in the CNS during immune responses to infection or injury.

“We found a key immune system target, called the NLRP3 inflammasome, lights up in Parkinson’s patients, with signals found in the brain and even in the blood,” said Woodruff, who is an associate professor in the faculty of medicine at Queensland.

An activated NLRP3 inflammasome was associated with the release of the pro-inflammatory molecule interleukin (IL)-1beta and ASC protein, which is also involved in the inflammatory response, in mouse cells, along with increased levels of activated caspase-1 — an enzyme responsible for the generation of active IL-1beta — in the substantia nigra of Parkinson’s patients.

The team found that low doses of MCC950, a small-molecule inhibitor of NLRP3, completely suppressed inflammasome activation in mouse microglia as well as ASC protein release. Importantly, once-daily, oral administration of MCC950 inhibited inflammasome activation, alpha-synuclein clumping, and loss of dopamine-producing neurons in a mouse model of Parkinson’s disease, while also easing their motor deficits.

“These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for [Parkinson’s],” the researchers wrote in the study.

Targeting microglia would represent a different strategy to that currently used by pharmaceutical companies, which have attempted to treat neurodegenerative disorders by blocking neurotoxic proteins that accumulate in the brain, said Matthew A. Cooper, PhD, one of the study’s authors and a researcher at the UQ Institute for Molecular Bioscience.

He also said that overactivation of the immune system, as well as brain inflammation and damage caused by microglia, can occur in Parkinson’s and other age-related diseases. “MCC950 effectively ‘cooled the brains on fire’, turning down microglial inflammatory activity, and allowing neurons to function normally,” he said.

“The findings provide exciting new insight into how the spread of toxic proteins occurs in Parkinson’s disease and highlights the important role of the immune system in this process,” said Richard Gordon, PhD, the study’s first author and an advance Queensland research fellow.

Gordon added that the team is now exploring approaches such as repurposing medications to target processes implicated in inflammasome-mediated disease progression.

The study was funded by The Michael J. Fox Foundation for Parkinson’s Research and Shake it Up Australia Foundation.

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Calcium Channels May Be Therapeutic Target in Parkinson’s, Stem Cell Study Suggests

calcium channels, Parkinson's

Targeting specific calcium channels in dopamine-producing neurons may be a therapeutic target for Parkinson’s disease, according to research involving cells derived from Parkinson’s patients.

The study, “T-type calcium channels determine the vulnerability of dopaminergic neurons to mitochondrial stress in familial Parkinson’s disease,” was published in Stem Cell Reports.

For most Parkinson’s patients, symptoms are idiopathic, or of unknown cause, making it difficult to understand the relationship between various factors that may cause disease. However, roughly 10% of patients show the familial incidence of Parkinson’s disease, which allows researchers to study the underlying mechanisms of disease in these patients, helping them understand common causes in all patients, as well as unravel potential therapeutic targets.

Prior generation of induced pluripotent stem cells (iPSCs) from patients with familial Parkinson’s successfully replicated the disease processes. 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.

Aiming to provide iPSCs-based ways to treat neurological diseases, Keio University School of Medicine and Eisai started a collaboration in 2013. Their joint research led to the generation of dopamine-producing neurons — progressively degenerated in Parkinson’s, leading to its motor symptoms — from familial Parkinson’s patients’-derived iPSC.

They also established a drug library of more than 1,000 existing compounds to screen treatment candidates.

The study, partially funded by Eisai, used neural progenitor cells, which differentiate into brain cells, including neurons, derived from two familial Parkinson’s disease patients with mutations in the PRKN gene (PARK2 type). PRKN is the most commonly implicated gene in young-onset Parkinson’s disease.

“The current procedure is more advanced in terms of simplicity and robustness for neuronal differentiation, enabling us to perform screening without complicated work,” researchers noted.

The approach enabled the efficient generation of dopamine-producing neurons in vitro, which, compared to healthy neurons, had reduced size of projections, as well as increased oxidative stress and apoptosis, or “programmed” cell death, as opposed to cell death caused by injury.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are harmful to cells and are associated with a number of diseases, including Parkinson’s.

Gene editing in iPSCs to create similar mutations led to the same disease-related alterations.

Researchers also found that Parkinson’s-derived neurons were more susceptible to mitochondrial stress induced by rotenone, an agrochemical that acts as a mitochondrial inhibitor. Mitochondria are small cellular organelles that provide energy and are known as cells’ “powerhouses”.

Screening their library enabled the identification of several compounds able to suppress rotenone-induced apoptosis, particularly T-type calcium channel blockers benidipine (used for the treatment of blood pressure) and ML218.

These particular calcium channels are present in many neuronal cells within the central nervous system. They help mediate calcium influx into neurons after passing electrical impulses to communicate among themselves.

These blockers also were able to lower stress-induced apoptosis in dopamine-producing neurons derived from patients with a different type of familial Parkinson’s (PARK6), caused by a mutation in the PINK1 gene. These neurons also had higher levels of T-type calcium channels.

“These findings suggest that calcium homeostasis in [dopamine-producing] neurons might be a useful target for developing new drugs for [Parkinson’s] patients,” researchers wrote.

“In summary, we have established a robust platform to model [Parkinson’s] in a dish and revealed an additional layer of the pathogenesis of PD, offering a potential therapeutic target,” they added.

Future work will use experimental approaches to model the brain in vivo and to have different types of brain cells in the same dish with the goal of validating these therapeutic targets.

Of note, six of the study’s authors are employees at Eisai.

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