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VCP, Enzyme in Protein Degradation, May Be Blood Biomarker of Early Stages of Parkinson’s, Study Suggests

VCP enzyme

Blood levels of valosin-containing protein (VCP) — an enzyme involved in protein degradation — may be used as a biomarker of preclinical and early clinical stages of Parkinson’s disease (PD), a study suggests.

Reduced levels of VCP in the blood were found in both animal models of the disease and untreated patients at preclinical and early clinical stages of Parkinson’s.

The study, “VCP expression decrease as a biomarker of preclinical and early clinical stages of Parkinson’s disease,” was published in the journal Scientific Reports.

Parkinson’s neurodegeneration begins many years before the emergence of its hallmark motor symptoms. It is thus crucial to identify biomarkers of presymptomatic, or preclinical, stages of the disease so that patients can benefit more from neuroprotective treatments, potentially preventing further damage.

The VCP enzyme, also known as p97 in mammals, has several cellular functions, including the maintenance of protein balance and quality. It is involved in the degradation of faulty proteins in several cellular compartments, including the mitochondria, known as the cells’ powerhouses.

Increasing evidence suggests that changes in VCP activity may contribute to the development of several neurodegenerative diseases.

Mutations in the VCP gene are responsible for the development of inclusion body myopathy with early-onset Paget disease and frontotemporal dementia, a condition that can affect the muscles, bones, and brain. VCP mutations also have been identified in people with other neurodegenerative disorders, such as Charcot–Marie–Tooth disease and amyotrophic lateral sclerosis (ALS).

Moreover, patients with neurodegenerative diseases and VCP mutations have been reported to show signs of Parkinson’s-like symptoms, including rigidity, tremor, and slowness of movements.

Together, the potential association of impaired VCP function with abnormalities in faulty proteins break-down, neurodegenerative conditions, and Parkinson’s-like symptoms suggest that changes in the enzyme may play a role in Parkinson’s development.

However, no studies have analyzed VCP levels during the early stages of idiopathic (sporadic) Parkinson’s — which is not caused by any mutations and is the most common form of the disease.

To learn more, a team of Russian researchers now evaluated the levels of VCP in a mouse model and in patients at the earliest stages of Parkinson’s.

The team analyzed VCP levels at different time points in both the blood and brain of mice injected with MPTP — a neurotoxin commonly used to induce the death of dopamine-producing neurons and create Parkinson’s models — that mimic early symptomatic stages of PD.

VCP levels also were measured in blood samples of 38 untreated and 14 treated patients with newly diagnosed Parkinson’s — considered to be early clinical stages — and in nine individuals with “predicted” Parkinson’s, considered late preclinical stages.

People with “predicted” Parkinson’s were those with an estimated PD diagnosis based on the presence of known predictors of the disease and who had a confirmed diagnosis two years later.

The researchers also analyzed blood samples of 23 people with neurological disorders other than Parkinson’s and 44 age-matched healthy individuals.

Data showed that VCP levels were similarly reduced in both mice and untreated patients at preclinical and early clinical stages of Parkinson’s disease.

The most significant changes in VCP levels observed in these mice were in the striatum and substantia nigra, two brain regions involved in Parkinson’s. Notably, after a significant reduction in VCP levels in these regions, there was an increase of VCP levels during the late presymptomatic stages, which the researchers hypothesized may be associated with compensatory mechanisms.

Changes in the enzyme levels in the substantia nigra were accompanied by similar alterations in the blood, suggesting that VCP blood levels “can be considered as biomarkers of the neurodegeneration of PD,” the researchers said.

In addition, untreated patients and people with “predicted” Parkinson’s had significantly lower VCP levels — by nearly two-fold — than healthy people. No significant differences were found between treated patients, people with other neurological diseases, and healthy volunteers.

These findings highlighted that a reduction in VCP levels is associated specifically with the development of Parkinson’s, and occurs in late preclinical and early clinical stages of the disease. It also showed that treatment influences the enzyme levels in Parkinson’s patients.

“These data suggest that a decrease in the relative levels of [VCP] might serve as a biomarker for the development of [disease] at the early clinical and preclinical stages of human PD [Parkinson’s disease],” the researchers said.

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Activating Cannabis Receptors Could Help Treat L-DOPA-induced Dyskinesia, Mouse Study Finds

dyskinesia

A compound that affects some of the same receptors in the brain as cannabis could help reduce dyskinesia — involuntary muscle movement — that develops following levodopa treatment in Parkinson’s disease, a new study done in mice suggests.

The mice were treated with HU-308, an agonist, or activator that binds to a cannabinoid receptor in the brain. It was found to reduce tremors without causing the “high” associated with cannabis.

Titled “Targeting the cannabinoid receptor CB2 in a mouse model of l-dopa induced dyskinesia,” the study was published in Neurobiology of Disease

Parkinson’s is characterized by the loss of neurons that make the neurotransmitter dopamine. Treatment with levodopa, or L-DOPA — a precursor to dopamine — has long been one of the gold standards for Parkinson treatment. However, this medicine can lead to uncontrollable movements, a condition called levodopa-induced dyskinesia, or LID.

The only treatment currently available for LID is Gocovri (amantadine). This is thought to reduce dyskinesia through a few different mechanisms, namely by reducing inflammation in the brain (neuroinflammation) and affecting glia, brain cells that serve a variety of specialized functions. Since glia function as the primary immune system in the brain, they play a role in neuroinflammation.

“If targeting neuroinflammation, and or glial signalling, offers a potential strategy, then cannabinoid based therapies could be an option for treating LIDs,” the researchers said. They explained that “cannabinoid-based therapies can exert effects on glia, are thought to suppress neuroinflammation, and have neuroprotective effects in preclinical animal models of several neurodegenerative disorders.”

However, cannabis itself is ill-suited to such therapeutic uses.

“Currently there is limited evidence about the effectiveness of medicinal cannabis,” Bryce Vissel, PhD, director of the Centre for Neuroscience and Regenerative Medicine at the University of Technology Sydney (UTS) and a study co-author, said in a press release. “One problem is that no cannabis preparation is the same and cannabis has numerous effects, some of which may not be beneficial in Parkinson’s disease.”

The compounds in cannabis act primarily via two chemical receptors in the brain, CB1 and CB2. Since CB1 is primarily responsible for the “high” cannabis can impart, which is not desirable in a medicine, the researchers investigated whether specifically activating CB2 could reduce LID without this adverse effect.

To test this, mice with modeled LID — essentially, modeled Parkinson’s disease followed by L-DOPA treatment to the development of LID — were treated with HU-308, a CB2 agonist (activator). Compared with mice that did not receive such treatment, LID was significantly decreased in the HU-308-treated mice, as evidenced both by behavioral observation and by decreased levels of FosB, a marker of LID in the brain.

To confirm that this effect was the result of CB2 activation, the researchers treated mice with both HU-308 and SR144528, which is an antagonist, or blocker, of CB2. This co-treatment eliminated the benefits imparted by HU-308 alone, suggesting that the effect is indeed due to CB2 activation.

In the same model, Gocovri also reduced LID, to a similar extent as HU-308. And, when both HU-308 and Gocovri were given simultaneously, the reduction in LID was greater than that seen with either treatment alone.

“The fact that amantadine [Gocovri] has its own set of side effects, may not work in the long term, and is still the only drug available on the market that is approved for dyskinesias makes our study really exciting,” said Sandy Stayte, PhD, a researcher at UTS and a study co-author.

“First, our study shows HU-308 is equally affective so a drug like HU-308 will be useful for those people who can’t take amantadine. Second, for those who can tolerate amantadine, taking the combination may have even greater benefits than taking either drug alone,” Stayte said. “That means we may end up with a much more powerful treatment than currently available by ultimately prescribing both.”

Further analysis revealed that both treatments — separately and combined — reduced neuroinflammation, as evidenced by decreased levels of inflammatory signaling molecules in the brain. Additionally, both treatments reduced the numbers of inflammatory glia cells.

“By reducing inflammation in the brain — such as with HU-308 — these immune cells [glia] can support normal neural function again, rather than inhibiting it,” Vissel said.

Interestingly, though, treatment with both HU-308 and Gocovri together did not affect neuroinflammation to a greater extent than either therapy alone. This suggests that the additive effect seen at the behavioral level may be due to other mechanisms. However, the team said their “measures in this paper are too rudimentary to explore these various mechanisms, and much further research is needed.”

Nonetheless, the study does support using CB2 agonists as a treatment strategy for LID.

The researchers said approximately 52-78% of patients may develop LIDs within 10 years of starting levodopa treatment.

“Accordingly, clinical trials investigating [CB2 agonists’] efficacy for neurodegenerative diseases is currently in high demand,” the investigators said.

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Immunotherapy Reduced Alpha-synuclein Clumps, Improved Dopamine Levels in Parkinson’s Mouse Model

antibodies and alpha-synuclein

Antibodies that selectively target the misfolded form of the alpha-synuclein protein — that which underlies the development of Parkinson’s disease — reduced the formation of alpha-synuclein clumps and improved dopamine levels in a mouse model. 

The study with that finding also provided a framework for screening  antibodies (immunotherapies) that target alpha-synuclein to identify those with the best therapeutic properties.

The study, “Characterization of novel conformation-selective α-synuclein antibodies as potential immunotherapeutic agents for Parkinson’s disease,” was published in the journal Neurobiology of Disease.

Nerve cell damage in Parkinson’s disease is caused by the build-up of toxic forms of the protein alpha-synuclein that forms clumps of misfolded proteins known as Lewy bodies.

Studies have found that reducing misfolded alpha-synuclein may be an effective therapeutic strategy for treating the disease. 

One idea is to create antibodies that specifically target misfolded alpha-synuclein, avoiding the problems associated with reducing the levels of properly folded, fully functioning alpha-synuclein.

This was the approach taken by a group of researchers at the University of Pennsylvania in Philadelphia. Their first step was to create and isolate antibodies that were highly selective for misfolded alpha-synuclein, then test the best candidate in a Parkinson’s mouse model to find out if the antibody had therapeutic potential. 

To create these antibodies, mice were injected with misfolded alpha-synuclein and the antibodies generated during the immune response were isolated and screened to find the best candidate. 

Brain sections from Parkinson’s patients with high numbers of Lewy bodies first were used to identify antibodies that selected pathological (disease-associated) alpha-synuclein.

The team hoped these antibodies may be used in humans, so those that bound to both mouse and human alpha-synuclein were preferred. 

Further testing found antibodies that bound to only the misfolded form of alpha-synuclein, but not the normal form. 

The final screen was to identify a candidate that prevented the development of alpha-synuclein pathology in neurons. Mouse neurons were treated with the previously selected antibodies and were exposed to toxic forms of human alpha-synuclein protein. The highest performing antibody, named Syn9048, reduced pathology [disease manifestation] by 97%.

As antibody treatments for Parkinson’s are likely to be given after symptoms emerge (when brain disease is already established), a mouse model was chosen to test the effectiveness of Syn9048 to reduce disease and rescue nerve cell function. 

Mice were injected with misfolded alpha-synuclein, which triggered nerve cell loss in the same areas of the brain as seen in Parkinson’s patients. Then they were given Syn9048 or a control antibody every week for six months.  

All mice gained weight in a similar manner, showing that the therapy was well-tolerated.

Examination of the mouse brains showed that Syn9048 reduced the aggregation of alpha-synuclein in areas related to Parkinson’s disease. 

Although Syn9048 was not successful in rescuing cells responsible for producing dopamine (dopaminergic), it increased dopamine levels in the brain, which suggested that the reduction of alpha-synuclein pathology may improve the function of remaining dopamine-producing neurons.

“Our study suggests that immunotherapy will not likely reverse existing pathology, but may halt the spread of pathology through the brain, preventing further motor and cognitive decline,” the researchers wrote.

“Future studies assessing brain-wide spread patterns could help predict the maximal possible benefit of immunotherapy and could be used to determine when during disease progression immunotherapy would need to be administered to be most efficacious,” they added. 

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Mouse-brain Computer Model Tracks Spread of Alpha-synuclein in Parkinson’s

alpha-synuclein protein

Researchers have developed a computer model of the mouse brain that integrates both Parkinson’s disease-related genetic risk factors and the animals’ brain networks to help them understand how abnormal alpha-synuclein protein spreads and how neurodegeneration progresses.

The study, “Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis,” was published in Nature Neuroscience. The research was funded by the National Institute on Aging.

In recent years, mutations in the gene coding for the leucine-rich repeat kinase 2 (LRRK2) have been identified as the most common cause of genetic Parkinson’s, accounting for 1%–2% of all cases and up to 40% in some ethnic groups.

Mutations in this gene usually result in the malfunctioning of lysosomes (special compartments within cells that digest and recycle different types of molecules).

Lysosomal dysfunction is involved in the formation of Lewy body protein aggregates and, therefore, neurodegeneration. One of the most common mutations found in the LRRK2 gene is called G2019S and occurs when a glycine is substituted by a serine at amino acid 2019. (Amino acids are the proteins’ building blocks.)

Evidence indicates that in neurodegenerative diseases misfolded proteins, such as alpha-synuclein, spread through the brain along anatomically connected networks, inducing progressive decline. In the laboratory, scientists have been able to reproduce the cell-to-cell transmission of disease-related molecules and consequent neuronal death.

However, it is still unclear which factors make cells vulnerable to disease and regulate the spread of misfolded.

To better understand the spatiotemporal pattern of misfolded protein spreading, researchers at the University of Pennsylvania have combined quantitative mapping of disease with network modeling of the mouse brain.

Researchers injected a toxic form of the alpha-synuclein protein into the dorsal striatum, a brain area involved in motor control, of 3-month-old mice and evaluated the protein buildup at 1, 3, and 6 months post-injection.

Alpha-synuclein was found to distinctly accumulate in different brain regions, including the substantia nigra, which is severely affected in Parkinson’s disease, the hippocampus (involved in learning and memory), dorsal striatum (involved in voluntary movement), motor cortex and somatosensory cortex (processes sensations). Higher concentrations were discovered in the brain regions connected to the injection site.

Three months after injection, alpha-synuclein had produced Lewy body-like cellular inclusions.

To understand how this protein spread in a context of disease, scientists developed a computer-based model using a map of the mouse brain and its inner neuronal pathways.

When the team compared the protein accumulations from the mouse brains to the computational model, alpha-synuclein was found to spread primarily along specific brain pathways. Nonetheless, some areas with alpha-synuclein buildup were not associated with those pathways, but instead to higher levels of SNCA, the gene that provides instructions for alpha-synuclein.

That discovery led the team to incorporate genetic variables into the  computer model.

Although the LRRK2 G2019S mutation is a known risk factor for developing Parkinson’s, mutated animals showed similar alpha-synuclein spreading patterns as non-mutated mice. Still, there were large regional differences in the degree and rate of alpha-synuclein pathology accumulation, namely within the hippocampus, substantia nigra and primary somatosensory cortex.

Importantly, mutated mice had no accumulation of alpha-synuclein if they were not injected with abnormal alpha-synuclein first, suggesting LRRK2 G2019S may not initiate disease by itself, but rather alter neuronal vulnerability to the disorder.

This hypothesis was confirmed when scientists observed a greater buildup of alpha-synuclein in specific brains regions of LRRK2 G2019S mutated mice, while those same areas were less vulnerable to abnormal cellular changes in non-mutated animals.

In conclusion, a brain network computer-based model that visualizes alpha-synuclein spreading and takes into account both brain connectivity and genetic background may become a reliable way to test different protein spreading scenarios. In the long-run, that should help investigators to better understand the processes behind neurodegenerative diseases such as Parkinson’s.

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Scientists Develop New Compound That Could Potentially Slow Parkinson’s Progression

S-181

Researchers have developed a new compound, called S-181, that can improve nerve cell function and decrease the build-up of disease-related harmful molecules by boosting the activity levels of the enzyme beta-glucocerebrosidase.

That enzyme’s function is known to be compromised in Parkinson’s disease.

The findings, “A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease,” were published in the journal Science Translational Medicine.

Mutations in the GBA1 gene are one of the most common genetic risk factors for Parkinson’s. The GBA1 gene contains instructions to produce an enzyme, called beta-glucocerebrosidase (GCase), which is active in lysosomes — special compartments within cells that break down and recycle different types of molecules.

If GCase fails to work as it is supposed to, toxic substances accumulate inside dopamine-producing cells, leading to the excessive inflammatory and neurodegenerative processes that are observed in Parkinson’s.

Therefore, and in theory, boosting GCase activity could potentially slow down disease progression.

Northwestern University scientists now took a different approach than the one currently attempted by researchers: instead of trying to fix the mutated version of the GCase enzyme, they attempted to increase the levels of its normal form in cellular and animal models of Parkinson’s.

The team developed a small-molecule modulator of GCase called S-181 and tested its function in dopaminergic neurons. These neurons were derived from induced pluripotent stem cells (iPSC) from sporadic or non-inherited (also known as non-familial) Parkinson’s patients, as well as from individuals with low GCase levels and with mutations in the GBA1, LRRK2, PARK7, or PARKIN genes — all of which have been associated with the neurodegenerative disorder.

iPSCs are master cells that can potentially produce any cell or tissue the body needs to repair itself. They are derived from either skin or blood cells, and then are reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of almost any type of human cell.

In this case, cells were derived from skin cells, also known as fibroblasts. Because they are derived from patients, the “novel daughter cells” will carry the same genetic defects as those found in the original cells.

S-181 binds to GCase and modulates its activity. Treating these patient-derived neurons with S-181 partially restored lysosomal function and lowered accumulations of Parkinson’s-related toxic molecules, including oxidized dopamine and glucosylceramide. It also decreased accumulations of alpha-synuclein, one of the main components of Parkinson’s hallmark protein deposits — called Lewy bodies.

Mice with a mutated GBA1 gene also were treated with S-181. The treatment boosted the activity of non-mutated GCase and reduced the production of barely active GCase-dependent harmful molecules, decreasing alpha-synuclein build-up in the brain.

“This study highlights wild-type GCase activation as a potential therapeutic target for multiple forms of Parkinson’s disease,” Dimitri Krainc, MD, PhD, chair of neurology and director of the Center for Neurogenetics at Northwestern University Feinberg School of Medicine, said in a press release.

“Our work points to the potential for modulating wild-type GCase activity and protein levels in both genetic and idiopathic forms of PD [Parkinson’s disease] and highlights the importance of personalized or precision neurology in development of novel therapies,” said Krainc, the study’s lead author.

Two years ago, a previous study by the same team showed that some of the molecular features of Parkinson’s are only present in human nerve cells and not in Parkinson’s animal models. Those findings illustrated the importance of investigating the disease mechanism and developing new medications using patient-derived neurons.

“It will be important to examine human neurons to test any candidate therapeutic interventions that target midbrain dopaminergic neurons in PD,” Krainc concluded.

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IL-17A Accelerates Brain Inflammation and Degeneration in Animal Models of Parkinson’s, Study Finds

Parkinson's and IL-17A

Interleukin-17A (IL-17A) — a molecule that is involved in immune and inflammatory responses — accelerates brain inflammation and degeneration in animal models of Parkinson’s disease, a study has found.

The research, “IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson’s disease,” was published in Brain, Behavior and Immunity.

Parkinson’s disease is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — together with brain inflammation caused by the over-activation of microglia, which are cells that support and protect neuronal cells, and are more reactive and proliferative than neurons.

“Our recent results show that Th17 cells contribute to PD [Parkinson’s disease] neuroinflammation and neurodegeneration. In revealing the mechanism by which Th17 cells injure dopaminergic neurons, we found that Th17 cells directly contact and kill neuronal cells by an interaction between two adhesion molecules expressed on membrane of these cells,” the investigators explained.

“Nevertheless, it needs clarification whether IL-17A … can directly damage dopaminergic neurons,” they added.

Of note, Th17 are the subtype of T-cells that produces IL-17 and have been associated with several inflammatory processes; a cytokine is a molecule that mediates and regulates immune and inflammatory responses.

In this study, a group of researchers from Nantong University in China set out to investigate how IL-17A might contribute to the development and progression of Parkinson’s in two different animal models of disease.

To trigger the onset of Parkinson’s, researchers treated mice with MPTP, a neurotoxin that induces brain inflammation, loss of dopaminergic neurons, and motor impairments, as seen in patients with the disease.

In parallel, rats were treated with MPP+, another neurotoxin closely related to MPTP, that also induces the onset of symptoms similar to those experienced by patients with Parkinson’s disease.

Results showed that treatment with both neurotoxins led to a disruption of the blood-brain barrier (BBB, a semipermeable membrane that isolates the brain from the blood that circulates in the body) and to a significant increase in the levels of IL-17A in the substantia nigra of both animal models.

To examine if BBB disruption in response to neurotoxins was sufficient to allow immune cells to enter into the animals’ brains, researchers injected them with T-effector cells that had been activated in a lab dish and measured their level of penetrance into the brain.

Of note, T-effector cells are T-cells that are immediately prepared to fight a pathogen because they have a “memory” of previously encountering it; these cells also include the Th17 subgroup.

Findings revealed that when injected into animals that had been treated with neurotoxins, T-effector cells were able to travel and enter into the animals’ brains. However, when injected into healthy animals that had never been treated with neurotoxins, T-effector cells failed to infiltrate the brain.

In addition, researchers found that when T-effector cells infiltrated the brain, they worsened animals’ symptoms; dopaminergic neurons were destroyed faster, microglia became over-activated faster and motor impairments were more severe.

Conversely, when researchers blocked the activity of IL-17A in rats’ brains (by injecting an anti-IL-17A antibody) they found that all Parkinson-like symptoms the animals experienced were significantly reduced. Likewise, when they performed a similar analysis in mice that had been genetically modified to lack IL-17A, they found that neuron degeneration, microglia activation and motor deficits were decreased greatly.

Additional in vitro experiments revealed that IL-17A had a direct impact on microglia activation, but not on neuron survival. According to the team, IL-17A requires the presence of microglia to accelerate neuronal loss.

Moreover, they discovered this effect was stronger in the presence of tumor necrosis factor alpha (TNF-a), a signaling molecule involved in immune and inflammatory responses, produced and released by activated microglia.

“[These] findings suggest that IL-17A accelerates neurodegeneration in PD [by inducing the] activation [of microglia] and at least partly [by promoting the release of other pro-inflammatory molecules, such as TNF-a],” the researchers wrote.

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Cellular Respiration Compound May Ease Symptoms, Reduce Neuronal Loss, Study Finds

cellular respiration compound

Delivering a compound called nicotinamide adenine dinucleotide to the striatum, a key brain region involved in motor control, can ease Parkinson’s symptoms and reduce dopamine-producing neuronal loss in a mouse model of the disease, a study finds.

The study, “Protective effects of β-nicotinamide adenine dinucleotide against motor deficits and dopaminergic neuronal damage in a mouse model of Parkinson’s disease,” was published in Progress in Neuropsychopharmacology & Biological Psychiatry.

Found in all living cells, nicotinamide adenine dinucleotide (NAD) is a coenzyme — or a substance that enhances the action of an enzyme — used for a series of body functions, including cellular respiration.

Although its Parkinson’s trigger remains to be identified, research indicates the causative mechanisms involve genetics, nonworking mitochondria (cells’ “powerhouses”) and oxidative stress — an imbalance between the production of free radicals and the ability of cells to detoxify them. Taken together, these molecular and cellular changes eventually cause the death of dopamine-producing neurons — the type of nerve cell that is gradually lost in Parkinson’s disease.

“In particular, it has been found that a reduced level of nicotinamide adenine dinucleotide (NAD) may cause mitochondrial dysfunction, DNA repair defects and neuronal death, resulting in many age-associated neurodegenerative pathologies,” the researchers said. That means that, in theory, restoring NAD levels could prevent the loss of dopamine-releasing neurons.

A Chinese team of researchers investigated whether an NAD injection into the striatum could alleviate Parkinson’s motor deficits and reduce dopaminergic neural loss in a rodent model of the disease.

Animals were given a NAD injection into the right striatum four hours before being injected with a neurotoxin called 6-hydroxydopamine (6-OHDA) into the same brain structure. This neurotoxin causes cellular dysfunction and the death of dopaminergic neurons. To a degree, it replicates Parkinson’s in a laboratory setting.

The rodents’ motor behavior was assessed four weeks after this procedure.

Compared to controls, NAD treatment eased Parkinson’s motor symptoms in animals injected with the 6-OHDA neurotoxin. In addition, brain tissue analysis revealed 6-OHDA-induced dopaminergic neuronal loss was significantly reversed by NAD injection. This was found both in the striatum and in the substantia nigra, another key brain region involved in motor function that is also affected in Parkinson’s.

Scientists then used cell culture technology to test if administering NAD to cells before they were damaged by 6-OHDA could protect them from cellular structural and molecular damage — including oxidative stress and mitochondrial problems.

Results revealed that the almost 50% reduction in cell viability caused by 6-OHDA was markedly reduced if cells were treated beforehand with NAD. The neurotoxin also caused changes in cell morphology (the size, shape and structure of cells), increased oxidative stress levels, and impaired mitochondrial function. Importantly, these alterations were all reversed following NAD pre-treatment.

“These results add credence to the beneficial role of NAD against parkinsonian neurodegeneration in mouse models of PD [Parkinson’s disease], provide evidence for the potential of NAD for the prevention of PD [Parkinson’s disease], and suggest that NAD prevents pathological changes in PD via decreasing mitochondrial dysfunctions,” the team concluded.

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CYP2D6 Enzyme Could Be Therapeutic Target in Parkinson’s, Study Suggests

CYP2D6

Blocking an enzyme that converts compounds derived from certain foods and tobacco in the brain may become a therapeutic target for people with Parkinson’s, according to a new study of mice.

The research, “Mitochondria-targeted cytochrome P450 CYP2D6 is involved in monomethylamine-induced neuronal damage in mouse models,” was published in the Journal of Biological Chemistry.

Prior research has shown that a synthetic opioid known as MPTP and related compounds can induce alterations similar to Parkinson’s in rodents and primates. It is thought that an enzyme called monoamine oxidase B (MAO-B), present in the nervous system’s glial cells, oxidizes MPTP into a toxic metabolite called MPP+. This metabolite is then transferred by dopamine transporter proteins to dopamine-producing neurons, which are typically affected in people with Parkinson’s disease.

Scientists at University of Pennsylvania had already found that the CYP2D6 enzyme, present in mitochondria — the cells’ power plants — also could be involved in transforming MPTP to MPP+.

“CYP2D6 is known to play a role in influencing the activity of a number of drugs,” Narayan Avadhani, PhD, the study’s senior author, said in a press release. These include antidepressants, antihypertensive medications, opioids, selective estrogen receptor modulators, and antidiabetic therapies, among other types of treatments.

The researchers focused on toxins called beta-carbolines and isoquinolines, which resemble MPTP and are produced by the body from compounds found in tobacco smoke, alcohol, and some foods. Prior studies indicated these toxins may induce Parkinson’s-related changes in rodents, but the mechanisms remained unclear.

Using a mouse model, the results showed that CYP2D6 activates beta-carbolines and isoquinolines inside dopamine-producing nerve cells, leading to cell damage, oxidative stress (cellular damage as a consequence of high levels of oxidant molecules) and impaired mitochondrial function, as occurs in Parkinson’s disease.

Then, the team observed that mice lacking CYP2D6 did not show the same disease-related alterations and that administering CYP2D6 blockers — quinidine or ajmalicine — could prevent neuronal damage.

Experiments in a type of cells that mimic human dopaminergic neurons, called Neuro2a, revealed that cells mainly producing mitochondria-targeted CYP2D6 were more sensitive to toxin-mediated respiratory impairment than those predominantly expressing endoplasmic reticulum-targeted CYP2D6. Of note, the endoplasmic reticulum is a key cellular structure in the production, folding, modification, and transport of proteins.

Upon exposure to the toxins, nerve cells expressing mitochondrial CYP2D6 also showed production of Parkin and Drp1, protein markers of autophagy — a cellular process in the removal of aggregated and toxic proteins, as well as other components — and mitochondrial fission.

The findings also suggest that targeting CYP2D6 may be a better approach than targeting MAO-B, which has led to mixed success in previous work. “We believe that mitochondrial CYP2D6 is the more direct drug target, which might prove better in treating idiopathic Parkinson’s,” Avadhani said.

Avadhani also said that ajmalicine, found in the medicinal plant Rauwolfia serpentine long had been used in India for treating mental disorders such as paranoia and schizophrenia.

“Mitochondrial targeting of such compounds is likely to be effective in treating Parkinson’s patients, and pursuing that is our future strategy,” he said.

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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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Plant Chemical Chrysin May Protect Against Parkinson’s-related Changes, Mouse Study Suggests

chrysin, protective effects

Chrysin, a chemical commonly found in plants, may ease behavioral, cognitive, and neurochemical changes in Parkinson’s disease, according to a mouse study.

The study, “Chrysin protects against behavioral, cognitive and neurochemical alterations in a 6-hydroxydopamine model of Parkinson’s disease,” was published in Neuroscience Letters.

Studies have confirmed the involvement of neuroinflammation and oxidative stress in the development of Parkinson’s disease. Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them, resulting in cellular damage as a consequence of high levels of oxidant molecules.

Both molecular phenomena have been implicated in the degeneration of dopamine-producing neurons — the type of nerve cell that is lost in Parkinson’s disease.

Chrysin is a naturally occurring flavone commonly found in fruits and vegetables. Evidence indicates the plant chemical has anti-allergic, anti-cancer, anti-inflammatory, and antioxidant properties.

A Brazilian team of researchers have now investigated the effects of a 28-day chrysin treatment (10 mg/kg/day, given orally) on a female aged mouse model of Parkinson’s disease.

Researchers first injected a neurotoxin called 6-hydroxydopamine (6-OHDA) into the mice’s right striatum — a brain region involved in voluntary movement control that is severely affected in Parkinson’s. This neurotoxin causes cellular dysfunction and death of dopaminergic neurons, enabling the molecular replication of Parkinson’s disease in a laboratory setting. Injected mice were all 20 months old, which is equivalent to a human age of more than 60 years.

Following the 28-day chrysin treatment protocol, the researchers performed memory, locomotor, and biochemistry tests these animals.

Compared with healthy control animals, chrysin was found to reduce the loss of dopamine and its metabolites (meaning “small products of metabolism”) in the striatum of the Parkinson’s mice, indicating the plant chemical may protect against disease-related dopamine metabolism degradation.

In line with the biological mechanism of Parkinson’s, 6-OHDA administration increased inflammatory responses by elevating levels of proinflammatory cytokines, or small proteins. Chrysin treatment prevented this response, supporting previous research on the compound’s anti-inflammatory properties.

Chrysin was also able to prevent the increase in oxidative stress levels that resulted from 6-OHDA injections. The animals’ antioxidant response also improved following treatment.

In addition, chrysin alleviated disease-related behavioral changes — which in mice manifests as rotational (circling) behavior — and cognitive deterioration including memory and spatial learning abilities. Researchers also noted that “age-related memory decline was partially protected by chrysin at a dose of 1 mg/kg, and normalized at the dose of 10 mg/kg.

“In the present study, chrysin was beneficial against behavioral, cognitive and neurochemical changes in a [Parkinson’s disease] model induced by 6- OHDA in aged female mice. Mechanisms underlying chrysin effects include decrease of oxidative stress and neuroinflammation, which eventually attenuates behavioral and cognitive impairments,” the researchers concluded.

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