Dietary Silicon-based Antioxidant Agent Prevents Parkinson’s in Mouse Study

antioxidant agent

A new dietary silicon-based antioxidant agent prevented neurodegeneration, and motor balance and coordination problems, in a mouse model of Parkinson’s disease.

By promoting production of the antioxidant molecule hydrogen, the agent  also was shown to prevent kidney failure in a rat model of chronic kidney disease, another condition associated with oxidative stress.

Oxidative stress is an imbalance between the production of potentially damaging molecules called reactive oxygen species (ROS), and the ability of cells to clear them with antioxidants.

“These are striking results that show that our Si [silicon]-based agent is effective in preventing the progression of chronic kidney disease and Parkinson’s disease in well-established animal models,” Shoichi Shimada, the study’s co-senior author at Osaka University, in Japan, said in a press release.

“Our findings could provide new insights into the clinical management of patients with these diseases, for which currently no curative approach exists,” he added.

The study, “Renoprotective and neuroprotective effects of enteric hydrogen generation from Si-based agent,” was published in the journal Scientific Reports.

Oxidative stress contributes to a number of conditions, including neurodegenerative diseases such as Parkinson’s and Alzheimer’s, as well as cancer, kidney failure, and diabetes.

In Parkinson’s, high levels of oxidative stress are thought to be closely associated with a dysfunction in mitochondria (the cell’s powerhouses), ultimately leading to the death of dopamine-producing, or dopaminergic, neurons.

Notably, not all ROS are alike, and while hydroxyl molecules are the strongest oxidant ROS and highly damaging to tissues, other ROS are part of the normal immune response.

Therefore, “eliminating only hydroxyl radicals is important to avoid disrupting normal physiological processes,” said Yuki Kobayashi, lead author of the study.

Several therapeutic approaches to reduce hydroxyl-based oxidative stress have been focused on hydrogen, a molecule that reacts only with hydroxyl molecules among ROS and can rapidly diffuse into tissues and cells.

However, approaches so far — such as inhaling hydrogen gas, drinking hydrogen-dissolved water, or injecting hydrogen-dissolved saline solution — have shown limited results, including in Parkinson’s disease.

“We wanted to develop a new dietary agent that efficiently enables the elimination of damaging hydroxyl radicals,” Kobayashi said.

To do so, the team of researchers at Osaka University developed a new antioxidant agent based on tiny particles (nanoparticles) of silicon, previously shown to produce hydrogen in contact with water.

The new oral agent was found to produce high levels of hydrogen for more than 24 hours in an environment similar to the intestine (the target organ, as from there hydrogen can enter circulation and spread throughout the body). These levels were the equivalent of drinking 22 liters of hydrogen-rich water.

To assess whether this was enough to have therapeutic benefits, the researchers looked at the effects of administering the agent to a mouse model of Parkinson’s disease and a rat model of chronic kidney disease.

The Parkinson’s mouse model was based on the injection of oxidopamine, a compound known to promote the loss of dopaminergic neurons in substantia nigra (a brain region rich in such neurons and affected in Parkinson’s), into one side of the mice’s brain.

Results showed that feeding oxidopamine-injected mice with a silicon-based agent-containing diet reduced the loss of dopaminergic neurons and prevented impairments in motor balance and coordination, compared with those fed a normal diet.

The researchers noted there was no remarkable difference in motor activity between the two groups, which may be explained by the partial neurodegeneration in the injected side of the brain and the presence of dopaminergic neurons in the non-injected side.

The agent also prevented oxidative stress and kidney damage in the chronic kidney disease rat model.

“Only hydrogen generated from Si-based agent is absorbed in the body, while Si-based agent is hardly absorbed, and therefore, Si-based agent is thought to be physiologically highly safe,” the researchers wrote, adding that no safety concerns were found in these mice.

These findings highlighted that the new dietary silicon-based antioxidant agent has neuroprotective and kidney-protective effects and may be “an innovative approach to treating a wide variety of diseases mediated by oxidative stress,” the researchers wrote.

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New Light-Controlled Tool Allows Study of Mitochondrial Damage in Live Neurons

mitochondrial damage

Scientists developed a new light-controlled tool that allows them to study the impact of mitochondrial damage in the live neurons of small transparent fish larvae, a study reports.

By allowing researchers to understand the mechanisms by which mitochondrial damage affects neurons, the new tool may potentially be used to develop new ways to restore the function of impaired neurons in patients with Parkinson’s, Alzheimer’s, and other neurodegenerative disorders.

The study, “Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity,” was published in the journal eLife.

Defects in mitochondria — the cell compartments responsible for the production of energy — found inside neurons have been linked to several neurodegenerative diseases. For instance, in patients with Parkinson’s or Alzheimer’s disease, studies have shown that dying neurons often have signs of mitochondria damage.

However, the exact mechanisms by which dysfunctional or damaged mitochondria contribute to neuronal death are still unclear. Technical challenges are part of the reason why research into this field has not yet advanced further.

“Gaining a better understanding of this process requires studying the impact of mitochondrial damage in live neurons, something that is still difficult to do,” the researchers wrote.

However, a team of scientists at the University of Pittsburgh may have found a way to overcome this limitation by using genetically modified transparent fish larvae along with a newly developed light-controlled tool that can be used to damage mitochondria found inside neurons.

They used fish larvae that had been genetically engineered to produce a protein called dL5 in mitochondria found inside their neurons, which can interact with a chemical compound called MG2I. When attached to each other and exposed to far-red light, dL5 and MG2I respond by producing reactive oxygen species (ROS) that trigger oxidative stress that damages mitochondria.

Oxidative stress is a type of cell damage caused by high levels of oxidant molecules, or ROS.

This means that each time fish larvae were exposed to far-red light, the mitochondria found inside their neurons were injured in a way that was directly proportional to the intensity of the light used.

“The really big first here is that we’ve got a way of targeting a one micrometer component of specific cells in a whole animal, with absolute precision in terms of where and when the damage happens and how much damage there is,” Edward Burton, MD, PhD, the lead author of the study, said in a news story.

“Compare that to coarser techniques, such as adding chemicals to the zebrafish’s water — there’s no way to control which cells get damaged,” added Burton, who is an associate professor of neurology at the University of Pittsburgh and a neurologist at the University of Pittsburgh Medical Center.

Using this system, the researchers observed that each time they exposed fish larvae to far-red light, they were no longer able to swim.

When they examined mitochondria found inside the animals’ neurons, they found they had swollen and lost their typical membrane ruffles where the production of adenosine triphosphate (ATP) — the small molecule used by cells as “fuel” — takes place.

Without ATP to sustain their needs, the neurons lost the ability to communicate with each other, and eventually started to die approximately 24 hours after the fish larvae had been exposed to far-red light.

“This new light-controlled tool could help to understand the consequences of mitochondrial damage, potentially revealing new ways to rescue impaired neurons in patients with Parkinson’s or Alzheimer’s disease,” the researchers wrote.

They have already created new genetically modified animals where dL5 is only produced in dopaminergic neurons — those that are lost over the course of Parkinson’s — which they hope will allow them to map the biochemical events leading up to neurodegeneration in Parkinson’s.

The new tool could also be used in other cell types to block the function of other cell compartments and study different types of disease.

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Antioxidant Nanoparticle Shows Promise in Lowering Oxidative Stress in Parkinson’s


Encapsulating the antioxidant small molecule ellagic acid into a nanoparticle that also has some antioxidant properties may be a promising approach to treat neurodegenerative conditions, such as Parkinson’s disease, in which oxidative stress plays a critical role, a study suggests.

In addition to reducing reactive oxygen species (ROS) — which when not cleared properly results in oxidative stress — and ROS-induced cell death better than any compound used alone, the approach also mitigated the toxicity of ellagic acid to cells, which has largely prevented its clinical development to date.

The study, “Chitosan-Ellagic acid Nanohybrid for mitigating rotenone-induced oxidative stress,” was published in the journal ACS Applied Materials and Interfaces.

Oxidative stress, or the imbalance between the production and clearance of toxic reactive species that are harmful to cells, such as ROS, is thought to play a key role in neurodegenerative diseases like Parkinson’s.

These toxic substances are increased as a result of deficient mitochondria (the cell’s powerhouses) and are thought to damage dopamine-producing neurons in Parkinson’s, eventually causing them to die.

Antioxidant small molecules found in nature, such as ellagic acid, are seen as a promising way to reduce the oxidative stress and nerve cell damage observed in patients, but because most of these molecules are not very soluble, patients would need to receive high doses, which can be toxic.

Researchers at The University of Texas at El Paso investigated whether encapsulating ellagic acid into a nanoparticle could reduce its toxicity while retaining its antioxidant properties. But instead of using a synthetic compound to create the particle, the team turned to chitosan, a biodegradable sugar molecule found in the hard outer skeleton of shellfish.

Notably, chitosan also has some antioxidant properties, which could improve the therapeutic effects of this approach.

After designing and developing their antioxidant nanoparticle, researchers tested their approach in cells cultured with rotenone, a pesticide known to inhibit the function of mitochondria and to induce oxidative stress. Rotenone often is used in animals to induce Parkinson’s-like symptoms.

Overall, the team found that the encapsulated formulation lowered the levels of toxic reactive species more efficiently, and prevented rotenone-induced neuronal cell death more than the nanoparticles alone or ellagic acid alone.

Also, while ellagic acid killed about 15% of cells in culture, nearly no cells died when cultured with the encapsulated formulation of this antioxidant.

“The results suggest that EA [ellagic acid] entrapped in chitosan-based nanoparticle system can serve as a better protecting agent against rotenone insult than EA alone,” the researchers wrote.

Importantly, the researchers noted that an ideal treatment should be able to release the active component in bursts, helping treat acute episodes of oxidative stress, and in a sustained manner given that reactive oxygen species are cleared up as they appear.

The team found that its nanoparticle system was able to do just that, releasing about 50% of ellagic acid in the first couple of hours, and then slowly releasing the remaining ellagic acid in the next 10 hours.

“This work creates a new type of bio-friendly drug-delivery vehicle made of recyclable materials,” Mahesh Narayan, PhD, who co-led the study, said in a press release. “The other special feature of this vehicle is that it can deliver the drug via two mechanisms: one rapid and the other a slow-release.”

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High Blood Levels of Liver Enzyme Linked to Sex-specific Parkinson’s Risk in Korean Study

sex-specific disease risk

Elevated blood levels of the liver enzyme gamma-glutamyltransferase (GGT), a marker for liver disease, was found to be associated with an increased risk of Parkinson’s disease in Korean women and a lower risk in Korean men, a large-scale study  found.

These sex-specific associations held after adjusting for factors that influence GGT levels, such as age, income status, body mass index (BMI), smoking habits, and alcohol consumption.

Although this study was conducted only in a Korean population, its results suggest that blood tests for GGT may be a useful marker for Parkinson’s disease risk.

The study, “Serum gamma-glutamyltransferase activity and Parkinson’s disease risk in men and women,” was published in Nature Scientific Reports

A process known as oxidative stress is thought to be one of the underlying mechanisms that lead to nerve cell damage or death in Parkinson’s. 

Oxidative stress occurs when there is an imbalance in the production of reactive oxygen molecules — called free radicals — and molecules that neutralize free-radicals, known as antioxidants. An excess of free radicals can oxidize proteins, lipids, and DNA, damaging the cellular components. 

Gamma-glutamyltransferase (GGT) is an enzyme primarily located in the membrane of liver cells, and is a blood marker for various conditions affecting the liver. Elevated levels of GGT in the blood are also associated with conditions like heart disease and stroke, as well as with metabolic syndrome (high blood pressure, high blood sugar, and excess body fat) and dementia.

GGT has also been implicated in oxidative stress, and given the connection between oxidative stress and Parkinson’s disease, GGT may also be a blood marker for Parkinson’s. 

To determine if such a relationship exists, researchers at Seoul National University College of Medicine in South Korea designed a study tracking millions of Korean citizens via use of that country’s National Health Insurance Service (NHIS) database.

Registration in the NHIS database has been mandatory for all citizens since 1989, and people over the age of 40 are advised to undergo a health screening every two years. The database accordingly holds detailed patient information, including demographics, blood tests (including of liver enzymes), health habits, body measurements, and factors like heart attack and stroke risk.

These data allowed investigators to follow almost 6.1 million adults (6,098,405) from 2009 through 2016. They recorded newly diagnosed cases of Parkinson’s to compare with levels of GGT from blood tests. 

During a median follow-up of 6.4 years, 20,895 Koreans developed Parkinson’s disease. Of these, 9,512 were men (0.33%) and 11,383 were women (0.35%). 

Higher levels of GGT in women were found to be significantly associated with an increased risk of Parkinson’s, while in men, elevated GGT in men was significantly linked to a lower risk of developing the disease. 

Women with the highest GGT levels had a hazard ratio of 1.33, with ratios above 1 representing a higher Parkinson’s risk. But men with the highest GGT levels had a hazard ratio of 0.67, indicating a lower risk. 

An initial analysis of the data found blood levels of GGT varied based on factors such as age, income status, body mass index (BMI), smoking, and alcohol consumption. 

When the team statistically adjusted for these factors, and for exercise, high GGT levels still showed a significant link to Parkinson’s disease risk, with that risk again being greater in women and lesser in men. 

This relationship remained after analyzing this sex-specific association across age groups, except for men older than 80. 

“The biological mechanism of serum GGT in these conditions is suggested to be associated with inflammation and oxidative stress,” the study noted. “Because abnormal protein aggregation, mitochondrial dysfunction resulting in oxidative stress, and neuroinflammation are the possible pathogenic mechanism of PD, GGT may be linked to the risk of PD development through inflammatory and oxidative stress reactions.”

As GGT levels may be related to the presence of fatty liver, investigators also looked for a possible link between GGT and obesity or metabolic syndrome and the risk of Parkinson’s.

For both men and women, a risk of Parkinson’s was seen to be greater in those who were obese or had metabolic syndrome. This finding was in line with previous research. 

But while no significant link between GGT levels and obesity with Parkinson’s was seen in men, a positive significant association was identified for women.

Estrogen, the primary female sex hormone, may be a reason for these sex-specific differences, the researchers said. Previous studies suggest this hormone is protective against Parkinson’s, but as women in middle-age go through menopause, their estrogen levels fall.

GGT blood levels are also known to be “inversely associated with estrogen,” the researchers wrote, speculating that “this could partially explain the sex-specific relationship between GGT and PD.”

They concluded, “this nationwide big data cohort analysis showed that the serum GGT level has a significant impact on the risk of PD, with a differential association in men and women.”

Further research is now needed to validate “serum GGT as a marker predicting PD risk in other ethnic populations.”

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Baicalin Protected Rats Against Parkinson’s Neurodegeneration

baicalin study

A bioactive agent called baicalin prevented neurodegeneration of Parkinson’s disease in rats by protecting against oxidative stress and neuronal death, according to a recent study.

The results, “Neuroprotective effect and mechanism of baicalin on Parkinson’s disease model induced by 6-OHDA,” were published recently in the journal Neuropsychiatric Disease and Treatment.

Although Parkinson’s trigger is unknown, research indicates its causative mechanism involves genetics, malfunction of mitochondria (the cells’ “powerhouses”), and oxidative stress — an imbalance between the production of harmful free radicals and the ability of cells to detoxify them, resulting in cellular damage.

Taken together, these molecular and cellular changes eventually result in the death of dopamine-producing neurons, the nerve cell type that is gradually lost in Parkinson’s disease.

Available treatments only ease disease symptoms, and there are currently no disease-modifying therapies that can delay or prevent Parkinson’s neurodegeneration.

Baicalin, a compound isolated from the Chinese skullcap‘s (Labiatae Scutellaria Linn Scutellaria baicalensis Georgi) dry roots, has been shown to have antibacterial, antiviral, anti-inflammatory, anti-tumor, cardiovascular, and neuroprotective activities.

Importantly, evidence shows that baicalin protects against dopaminergic neuronal damage induced by either rotenone or MPTP, two neurotoxins that are commonly used to replicate Parkinson’s in animal models.

A Chinese team of researchers now investigated the effects of baicalin on a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson’s disease. Like rotenone and MPTP, 6-OHDA induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms.

Baicalin was given in one of three doses: low (50 mg/kg), medium (100 mg/kg), or high (150 mg/kg). Following baicalin continuous administration for eight weeks, scientists assessed animals’ fatigue, motor coordination, voluntary movement, anxiety and exploratory behavior on a weekly basis. Neuronal changes following baicalin treatment also were evaluated.

Baicalin was found to improve rats’ coordination and voluntary movement. The compound also prevented oxidative stress-related neuronal damage and death, and promoted the release of neurotransmitters to regulate dopamine-dependent communication within the rats’ brain by regulating six small metabolic molecules: N-acetyl-aspartate (NAA), aspartate, glutamate, gamma-aminobutyric acid, glycine, and taurine.

“NAA is a hallmark of neuronal changes in the brain, and a decreased level suggests a loss or dysfunction of neurons,” researchers noted. On the other hand, glutamate is mainly involved in signal transmission, and learning and memory formation.

Further analysis revealed rats with Parkinson’s had low levels of N-acetyl-aspartate (NAA) and high levels of glutamate in the striatum (a brain region involved in motor control). After continuous administration of baicalin for two months, NAA and glutamate concentrations in the striatum changed in a dose-dependent manner to almost similar levels of those seen in healthy animals: higher baicalin doses resulted in increased metabolite concentrations.

Importantly, the team believes that both NAA and glutamate levels could be potential diagnostic biomarkers to assess neurodegeneration in the context of Parkinson’s disease.

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Dosing Begins in Phase 2 Trial of CNM-Au8, Potential Therapy for Dopaminergic Neurons

Parkinson's pilot trial

A pilot Phase 2 study evaluating CNM-Au8, an investigational Parkinson’s treatment aiming to protect nerve cells, has started dosing patients, the therapy’s developer, Clene Nanomedicine, announced.

The open-label REPAIR-PD (NCT03815916) clinical trial is enrolling up to 24 people, ages 30 to 80 and diagnosed within the past three years, at its one site at the University of Texas Southwestern Medical Center.

“We are excited to be advancing CNM-Au8 clinically into Parkinson’s patients starting with the REPAIR-PD Phase 2 study” Rob Etherington, president and CEO of Clene, said in a press release.

Parkinson’s disease is characterized by the death of dopaminergic neurons in two brain regions, the striatum and the substantia nigra. These nerve cells rely on large amounts of energy to function, which is provided by mitochondria, the cell’s powerhouses. Failure to provide the energy that cells need contributes to their death.

Oxidative stress, an imbalance between the production of harmful free radicals and the ability of cells to detoxify them, is another hallmark of Parkinson’s disease. These free radicals, or reactive oxygen species, are produced during certain metabolic reactions that involve mitochondria, and can damage cells.

CNM-Au8 is a suspension of nanocrystalline gold designed to increase the production of energy. Specifically, it works by increasing the speed of conversion between two molecules — nicotinamide adenine dinucleotide (NADH) to its oxidized form (NAD+) — resulting in greater production of energy in the form of ATP (adenosine triphosphate, an energy-carrying molecule of cells).

In addition, CNM-Au8 has antioxidant properties that may help to protect cells against oxidative stress.

Preclinical (in the lab) data showed that CNM-Au8 aided the survival of dopaminergic neurons, and helped prevent the loss of mitochondria.

In a rat model of Parkinson’s disease, treatment with CNM-Au8 improved the animal’s motor activity compared to control (untreated) mice. Of note, rats treated with CNM-Au8 in this test showed better results than did rats given carbidopa/levodopa, a standard Parkinson’s therapy.

“Our preclinical data with CNM-Au8 demonstrated improvements in neuronal bioenergetics, which may improve the survival of dopaminergic neurons in patients with PD [Parkinson’s disease], thereby helping slow the progression of this devastating disease,” Etherington said.

A Phase 1 clinical trial involving healthy volunteers (NCT02755870) found CNM-Au8 to be safe.

In the REPAIR-PD study, patients will first undergo a four-week screening period, after which they will drink two ounces of CNM-Au8 daily each morning for 12 weeks. Treatment will be followed by a four-week follow-up period.

The study’s primary outcome is to determine improvements in oxidative stress in the central nervous system (brain and spinal cord), assessed by the ratio of NAD+/NADH measured using magnetic resonance spectroscopy (MRS).

Additional (secondary) measures include assessing the effects of CNM-Au8 on energy production, and nerve cell metabolism.

“The objective of the REPAIR-PD Phase 2 study is to demonstrate improvements in brain bioenergetic metabolism in Parkinson’s disease patients treated with CNM-Au8. Participants will undergo 31phosphorous magnetic resonance spectroscopy (31P-MRS) imaging to show how treatment with CNM-Au8 results in improvements in brain metabolic and membrane biomarkers,” said Robert Glanzman, MD, chief medical officer of Clene.

Results from the REPAIR-PD trial are expected by mid-2020.

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Model of Cell Aging and Damage May Help in Understanding Parkinson’s Onset

cells and aging

A newly created model helps to clarify the processes by which cells grow old and die, and which are known to be involved in the onset of neurodegenerative disorders like Alzheimer’s and Parkinson’s disease.

The study describing this model, “Proteostasis collapse is a driver of cell aging and death,” was published in PNAS.

To remain healthy, cells must be able to produce proteins and chaperone them: keeping proteins correctly folded, and destroying those that aren’t.

But as cells age, oxidative stress — an imbalance between reactive and inflammatory free radicals and the ability of cells to detoxify them — slowly leads to the accumulation of irreparably damaged proteins inside cells that eventually overwhelm their “quality control” mechanisms.

“Irreparably damaged proteins accumulate with age, increasingly distracting the chaperones from folding the healthy proteins the cell needs. The tipping point to death occurs when replenishing good proteins no longer keeps up with depletion from misfolding, aggregation, and damage,” the researchers wrote.

Investigators with the Laufer Center for Physical & Quantitative Biology at Stony Brook University created a model that is able to predict the lifespan of the round worm Caenorhabditis elegans, an animal model often used in aging studies, based on its protein quality control mechanisms.

In their study, scientists showed their model’s predictions matched the results of experiments they performed on round worms to assess the effects of oxidative damage on the animals’ lifespan.

In one experiment, they found that animals raised at a temperature of 20 degrees Celsius (about 68 degrees Farhenheit) had an average lifespan of 20 days. Worms were raised at higher temperatures and in the presence of free radicals (byproducts of oxidative stress), however, had lifespans of only a few hours.

“As the cell is stressed by heat, proteins unfold, misfold, and aggregate. Chaperones are recruited, but with age, the synthesis [production] of ‘good protein’ and the chaperoning of those spontaneously unfolding ultimately succumb to damage levels, at which bad protein becomes overwhelming,” the researchers said.

Their work also found that mutant animals with more chaperones or proteasomes — a complex of enzymes responsible for the destruction of unnecessary or damaged proteins — lived longer.

All these findings were in agreement with the foundations of their model, which stated that oxidative stress and protein instability increase with age and are the root cause of cell degeneration.

“This modeling is unique by being mathematically detailed and describing a broad range of cellular processes across the cell’s whole proteome [all proteins found in a cell],” Ken A. Dill, PhD, a distinguished professor and director of the Laufer Center for Physical & Quantitative Biology, and a study co-author, said in a news release.

“Often, aging-related studies look at the effects of one or two proteins at a time, rather than seeking, more generally, the cellular aging mechanism itself,” Dill added.

This study also sets the foundation for future research into the molecular origins of aging disorders associated with protein misfolding, such as Parkinson’s.

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CRISPR/Cas9’s Potential in Better Understanding and Treating Parkinson’s Focus of Review Study

gene editing and disease

In a recent review, scientists highlight the potential of gene editing technologies like CRISPR/Cas9 to not only understand the molecular mechanisms behind Parkinson’s disease, but also identify new targets for treatment.

The review study, “Interrogating Parkinson’s disease associated redox targets: Potential application of CRISPR editing,” was published in the journal Free Radical Biology and Medicine.

One of the hallmarks of PD is the loss of dopamine-producing neurons in the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in PD. This occurs due to the clustering of a protein called alpha-synuclein in structures commonly known as Lewy bodies inside neurons.

Parkinson’s is complex and multifactorial disease, with both genetic and environmental factors playing a role in either triggering or exacerbating the disease.

Genetic causes can explain 10% of all cases of PD —  called familial PD –, meaning that in the majority of the cases (sporadic PD) there is an interplay between genetics and environmental risk factors.

Researchers at Sechenov University in Russia and the University of Pittsburgh reviewed the role of metabolic pathways, especially problems with mitochondria — cells’ powerhouses — and iron accumulation, as well as mechanisms in cell death (called apoptosis and ferroptosis) in the development and progression of Parkinson’s disease.

These processes were discussed in the context of genome editing technologies, namely CRISPR/Cas9 — a technique that allows scientists to edit genomes, inserting or deleting DNA sequences, with precision, efficiency and flexibility.

“Empirical research has established many potential metabolic abnormalities that may represent the specific key mechanisms of PD pathogenesis. However, the diversity of these findings and the lack in understanding the connections between them slow down the progress in the development of specific treatments,” the researchers wrote. These abnormalities may be “[a]mong [the] many potentially important targets for CRISPR/Cas9 based research.”

“CRISPR is a promising technology, a strategy to find new effective treatments to neurodegenerative diseases,” Margarita Artyukhova, a student at the Institute for Regenerative Medicine at Sechenov and the study first author, said in a press release.

Mitochondria don’t work as they should in people with PD, resulting in shortages of cellular energy that cause neurons to fail and ultimately die, particularly dopamine-producing neurons. Faulty mitochondria are also linked to the abnormal production of reactive oxygen species, leading to oxidative stress — an imbalance between the production of free radicals and the ability of cells to detoxify them— that also damages cells over time.  

Because mitochondrial dysfunction is harmful, damaged mitochondria are usually eliminated (literally, consumed and expelled) in a process called mitophagy — an important cleansing process in which two genes, called PINK1 and PRKN, play crucial roles. Harmful changes in mitophagy regulation is linked with neurodegeneration in Parkinson’s.

Previous studies with animal models carrying mutations in the PINK1 and PRKN genes showed that these animals developed typical features of PD – mitochondrial dysfunction, muscle degeneration, and a marked loss of dopamine-producing neurons.

PINK1 codes for an enzyme that protects brain cells against oxidative stress, while PRKN codes for a protein called parkin. Both are essential for proper mitochondrial function and recycling by mitophagy. Mutations in both the PINK1 and PRKN gene have been linked with early-onset PD.

However, new research suggests that the role of PINK1 and PRKN in Parkinson’s could be more complex and involve other genes — like PARK7  (DJ-1), SNCA (alpha-synuclein) and FBXO7  — as well as a fat molecule called cardiolipin.

CRISPR/Cas9 genome editing technology may be used to help assess the role of different genetic players in Parkinson’s disease, and to look for unknown genes associated with disease progression and development. Moreover, this technology can help generate animal and cellular models that might help scientists decipher the role of certain proteins in Parkinson’s and discover potential new treatment targets.

Iron is another important metabolic cue in Parkinson’s. While it’s essential for normal physiological functions, excessive levels of iron can be toxic and lead to the death of dopamine-producing neurons in the substantia nigra.

Iron may also interact with dopamine, promoting the production of toxic molecules that damage mitochondria and cause alpha-synuclein buildup within neurons.

CRISPR/Cas9 technology can be used to help dissect the role of proteins involved in iron transport inside neurons, which in turn may aid in designing therapies to restore iron levels to normal in the context of Parkinson’s disease.

Finally, researchers summarized evidence related to the role of two cell death pathways — ferroptosis and apoptosis — in PD. Ferroptosis is an iron-dependent cell death mechanism by which iron changes fat (lipid) molecules, turning them toxic to neurons. This process has been implicated in cell death associated with degenerative diseases like Parkinson’s, and drugs that work to inhibit ferroptosis have shown an ability to halt neurodegeneration in animal models of the disease.

Apoptosis refers to a “programmed” cell death mechanism, as opposed to cell death caused by injury. Both apoptosis and ferroptosis speed the death of dopaminergic neurons.

CRISPR/Cas9 may help to pinpoint the key players in cell death that promote the loss of  dopaminergic neurons in Parkinson’s disease, while understanding the array of proteins that are involved in these processes.

“These insights into the mechanisms of PD pathology [disease mechanisms] may be used for the identification of new targets for therapeutic interventions and innovative approaches to genome editing, including CRISPR/Cas9,” the researchers wrote.

Genome editing technology is currently being used in clinical trials to treat patients with late-stage cancers and inherited blood disorders, Artyukhova notes in the release.

These “studies allow us to see vast potential of genome editing as a therapeutic strategy. It’s hard not to be thrilled and excited when you understand that progress of genome editing technologies can completely change our understanding of treatment of Parkinson’s disease and other neurodegenerative disorders,” she adds.

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Olive Oil Compound Tyrosol May Be Beneficial Against Parkinson’s, Worm Study Suggests

olive oil tyrosol

A compound found in extra virgin olive oil may have beneficial effects in Parkinson’s disease, a study in the nematode worm Caenorhabditis elegans shows.

Researchers say the compound Tyrosol reduced oxidative stress and induced the expression of different protective genes in a model of Parkinsonism.

Titled “Tyrosol, a simple phenol from EVOO, targets multiple pathogenic mechanisms of neurodegeneration in a C. elegans model of Parkinson’s disease,” the study was published in the journal Neurobiology of Aging.

Tyrosol, found in extra virgin olive oil and argan oil, is a phenol, a class of organic molecules. Some have been shown to have beneficial effects against neurodegenerative diseases — disorders in which brain nerve cells, or neurons, eventually die. Tyrosol, in particular, has antioxidant properties.

In previous publications, the researchers behind this new study had shown that tyrosol delayed aging and reduced markers of cellular stress in wild-type Caenorhabditis elegans (C. elegans) —smooth-skinned, unsegmented worms. This made them wonder whether tyrosol might be beneficial in neurodegenerative diseases, specifically Parkinson’s.

To find out, the researchers used a C. elegans model of Parkinson’s called the NL5901 strain.

They found that, compared with untreated worms, treatment with tyrosol significantly increased the lifespan (18.67 vs. 21.33 days) of these animals. Motility — the organism’s ability to move independently — was significantly increased at the ninth day of the worm’s life (7.7 vs. 20.9 activity counts per half hour). However, it was similar at all other time points, with both treated and untreated worms developing paralysis by 11 days of age.

This treatment also significantly reduced the number of aggregates, or clumps, of the protein alpha-synuclein (58.72 vs. 22.63 aggregates per worm), which are a hallmark of Parkinson’s disease. The tyrosol also significantly decreased the levels of molecules that can damage cellular structures and DNA, called reactive oxygen species (124.5 vs. 12.06 arbitrary fluorescence units).

The results suggest that tyrosol treatment has an effective antioxidant effect in these animals.

Researchers note that oxidative stress results from an imbalance between the production of free radicals and the ability of cells to detoxify them. These reactive oxygen species are harmful to the cells and are associated with a number of diseases, including Parkinson’s.

Tyrosol treatment significantly increased the expression of a few proteins that are known to help cells protect themselves from damage, like heat shock proteins.

The researchers then turned to another C. elegans strain, UA44, to examine the effects of tyrosol on dopaminergic neurons — neurons that produce the chemical messenger dopamine — that are mainly lost in Parkinson’s disease.

At two weeks of age, significantly more of the tyrosol-treated worms had their dopaminergic neurons intact compared with untreated worms (80% vs. 45.33%). That suggests that tyrosol treatment reduced neurodegeneration — likely, at least in part, through the same mechanisms.

Based on these results, the researchers concluded that tyrosol might be “a suitable candidate as a nutraceutical compound” for Parkinson’s disease. A nutraceutical is a food or part of a food that provides medical or health benefits, including the prevention and treatment of disease.

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Plant Antioxidant Seen to Aid Mitochondria and Ease Motor Problems in Early Parkinson’s Study

plants and antioxidants

Alpha-arbutin — an antioxidant found in plants such as blueberry bush — may restore mitochondrial function in nerve cells and ease the motor disabilities associated with Parkinson’s disease, according to a preclinical study from China.

Its results point to alpha-arbutin as a potential therapeutic compound for Parkinson’s and other disorders linked to problems in mitochondria, a cell’s energy source.

The study, “α-Arbutin Protects Against Parkinson’s Disease-Associated Mitochondrial Dysfunction In Vitro and In Vivo,” was published in the journal NeuroMolecular Medicine.

Parkinson’s disease is characterized by the degeneration and death of a specific group of nerve cells — called dopaminergic neurons —  in the substantia nigra, a region of the brain that regulates muscle movement and coordination. To work as intended, these nerve cells require large amounts of energy, which is provided by mitochondria.

Mitochondria are small organelles inside cells that, apart from being a cell’s “powerhouse,” are also the main producers of free radicals, or reactive oxygen species, which are associated with oxidative stress. Oxidative stress results from an imbalance between the production of free radicals and a cell’s ability to detoxify them, leading to cellular damage.

Increasing evidence suggests that both mitochondrial dysfunction and oxidative stress contribute to the degeneration of dopaminergic neurons seen in Parkinson’s disease. Compounds that can reduce mitochondrial dysfunction or oxidative stress may protect these neurons, and be potential therapies for Parkinson’s.

Alpha-arbutin, a natural compound extracted from plants of the heath family (Ericaceae) — which includes blueberry and bearberry bushes, and cranberry bogs — was shown to have antioxidative properties and to suppress the production of a key mediator of oxidative stress in Parkinson’s disease.

Researchers set out to evaluate the therapeutic potential of alpha-arbutin in two established preclinical disease models.

The first model involved nerve cells grown in the lab and treated with rotenone, a pesticide known to impair mitochondrial function, promote their production of free radicals, cause cellular death, and lead to parkinsonian features.

Giving alpha-arbutin to nerve cells before rotenone (pre-treatment) eased this pesticide’s toxic effects, suppressing free radical production and increasing the levels of antioxidative molecules. This worked to promote an oxidative balance, leading to fewer dead nerve cells.

Pre-treatment with alpha-arbutin also attenuated rotenone-induced mitochondrial damage to the cells and restored their ability to engage in autophagy, a vital cellular recycling system that removes or recycles unnecessary or dysfunctional components. Rotenone suppresses this natural process, damaging and killing cells.

These results suggested that alpha-arbutin’s neuroprotective effects were associated with a reduction in oxidative stress, and the maintenance of mitochondria function and autophagy processes.

Researchers then evaluated whether alpha-arbutin could ease Parkinson’s-associated symptoms and mitochondrial damage in fruit flies lacking the PRKN gene. Mutations in PRKN are known to trigger mitochondrial dysfunction, loss of dopaminergic neurons, and early-onset Parkinson’s disease.

Feeding these mutated flies alpha-arbutin significantly improved their climbing ability and wing posture, whose pre-treatment abnormalities are considered characteristic disease symptoms. The treatment also restored their mitochondrial structure and increased their energy production.

These findings, the researchers said, show for the first time that alpha-arbutin is able to not only significantly reduce rotenone-induced oxidative stress and mitochondrial dysfunction in nerve cells, but can also rescue motor problems and mitochondrial abnormalities in an animal model of Parkinson’s disease.

“Naturally derived-antioxidants might serve as a new class of therapeutic options for PD [Parkinson’s disease],” the researchers wrote.

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