Study Suggests Mechanism Behind Levodopa-induced Dyskinesia in Parkinson’s


The protein RasGRP1 is a key culprit for involuntary movements that arise from dopamine replacement therapies used to treat Parkinson’s disease, a new study done in animals suggests.

Targeting this protein may be a therapeutic strategy to prevent these motor problems, while still receiving the benefits of treatment.

The study, “RasGRP1 is a causal factor in the development of l-DOPA–induced dyskinesia in Parkinson’s disease,” was published in Science Advances.

Parkinson’s disease is caused by the death of nerve cells in the brain that make the neurotransmitter dopamine. Therapies designed to increase the amount of dopamine in the brain, including levodopa (l-DOPA) and its derivatives, are staples of Parkinson’s treatment.

Although the effectiveness of these treatments is well-established, long-term use is associated with the development of involuntary movements called dyskinesia. However, exactly which molecular mechanisms are responsible for this side effect is not clear.

Previous research implicated a protein called Rhes in the development of  dyskinesia. In the new study, researchers examined the role of a related protein, RasGRP1 (Ras-guanine nucleotide-releasing factor 1). This protein is known to activate Rhes, and it has been shown to be active in certain blood cells. But its role in the brain is less clear.

Researchers first used a mouse model of Parkinson’s in which dopamine-producing neurons are killed by means of a specific toxin (6-hydroxydopamine). The researchers modeled Parkinson’s both in wild-type mice and in mice that had been genetically engineered to lack RasGRP1.

Both types of mice displayed similar Parkinson’s-like symptoms, and l-DOPA treatment resulted in similar improvement in these symptoms in both types. However, mice lacking RasGRP1 displayed significantly fewer abnormal involuntary movements with long-term l-DOPA treatment.

Additionally, in wild-type mice, l-DOPA treatment induced significantly higher levels of RasGRP1 in the mice’s brains. This finding also was replicated in a macaque (a type of monkey) model of Parkinson’s disease.

“Since monkey model for PD [Parkinson’s disease] can mimic more signs and symptoms of human PD, our finding strengthens the translational relevance of RasGRP1 in PD treatment,” the researchers wrote.

Additional biochemical studies indicated that RasGRP1 is involved in dyskinesia through the activation of the proteins mTOR and ERK (as well as other associated proteins).

These proteins have been implicated previously in l-DOPA-induced dyskinesia (LID). However, they play many important roles in different types of cells throughout the body, so it’s difficult to therapeutically target them without significant side effects. In contrast, the lack of functional RasGRP1 in mice did not result in noteworthy physiological problems, apart from some mild deficits related to the development of cells in the thymus, an organ that’s part of the immune system.

Because of this, “… we think that blocking RasGRP1 with drugs, or even with gene therapy, may have very little or no major side effects,” study co-author Srinivasa Subramaniam, PhD, a professor at Scripps Research, said in a press release.

Since mice and humans are biologically distinct in many important respects, further research will be needed to determine the safety profile of treatments intended to block RasGRP1. Nonetheless, this study provides a theoretical foundation for the possible utility of such treatment strategies.

“There is an immediate need for new therapeutic targets to stop LID,” Subramaniam said. “The treatments now available work poorly and have many additional unwanted side effects. We believe this represents an important step toward better options for people with Parkinson’s.”

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Study Shows Age-dependent Spread Of Alpha-synuclein From Gut to Brain in Mice

gut Parkinson's alpha-synuclein

Aggregates of the Parkinson’s disease-associated protein alpha-synuclein can spread from the gut to the brain in mice, but this process is dependent on aging, likely as a result of altered protein dynamics, a new study suggests.

The study, “Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice,” was published in Nature Neuroscience.

Parkinson’s disease is characterized by aggregates of alpha-synuclein in the nervous system, particularly in dopamine-producing neurons in the brain. However, how these aggregates form in the first place isn’t fully understood.

One proposed hypothesis is that these aggregates don’t initially form in the brain, but in the enteric nervous system (ENS) — the nervous system of the gut. This hypothesis is supported by the fact that many people with Parkinson’s experience gastrointestinal symptoms, such as constipation, years before the onset of motor symptoms. The idea is that, from the gut, the aggregates could “spread up” to the brain through the vagus nerve.

“The vagus nerve is a physical connection between neurons in the gut and neurons in the brain,” study co-author Collin Challis, PhD, a former postdoctoral researcher at California Institute of Technology (Caltech), said in a press release. “If these damaging protein clusters first originate in gut neurons, then in the future we may be able to diagnose [Parkinson’s disease] earlier and potentially use gene delivery to restore functions to the cells so that they can clean up the aggregates.”

In the new study, researchers injected alpha-synuclein aggregates into the lining of the intestinal tract in mice. This led to numerous Parkinson’s-associated changes in the gut, including increased production of inflammatory molecules (e.g. IL-6), gastrointestinal dysfunction, and increased activation of neurons in the ENS, indicating an inflammatory response.

The researchers then looked to see whether the aggregates had spread into the central nervous system (CNS, comprising the brain and spinal cord). Interestingly, initial experiments did not reveal significant aggregate accumulation in the CNS, nor were there sustained motor impairments of the sort that would be expected if this system was modeling Parkinson’s disease.

But, crucially, these experiments were done in young adult mice (8-10 weeks old), and the biggest risk factor for developing Parkinson’s is aging. Thus, the researchers repeated the experiment in older (16-month-old) mice.

In these mice, as in the younger mice, injecting alpha-synuclein into the gut lining led to gut dysfunction. But, unlike in the young mice, older mice also developed motor deficits resembling Parkinson’s disease. Furthermore, the older mice did have alpha-synuclein aggregates in their brainstems, supporting the idea that the aggregates “spread up.”

Additionally, the older mice had significantly reduced levels of dopamine in their brains, which was not observed in the younger mice following alpha-synuclein injection.

The reason for this age-related difference may come down to how protein-regulating systems in the body change with age.

The researchers demonstrated that older mice express significantly less of the gene GBA1, which encodes for the protein glucocerebrosidase (GCase). This protein plays a critical role in the molecular machinery that cells use to recycle proteins, so the researchers proposed that the age-associated decrease in GCase levels could allow alpha-synuclein aggregates to spread in a way that is limited in younger animals.

In keeping with this idea, the researchers found that, when they increased GCase levels in the guts of young adult mice through gene therapy using a variant of adeno-associated virus (AAV) as a delivery system, gut-related problems associated with alpha-synuclein were diminished, though not entirely resolved. As such, although GCase dysfunction probably isn’t the only factor, it likely plays a role in alpha-synuclein pathology.

“Our results propose mechanisms that may underlie the etiology of sporadic [Parkison’s disease] and highlight GBA1 as a therapeutic target for prodromal [early], peripheral synucleinopathy,” the researchers wrote.

“Interestingly,” they noted, “[disease-causing alpha-synuclein] also inhibits GCase function.” As such, it’s possible that there is a feedback loop wherein increasing alpha-synuclein leads to decreased GCase function, which in turn leads to further increases in alpha-synuclein, until a threshold is crossed, spilling over into disease.

“Mutations in the gene that encodes GCase are responsible for Gaucher disease and a risk factor in [Parkinson’s disease],” said Viviana Gradinaru, PhD, a professor at Caltech and co-author of the study. “Our work shows that this gene can be delivered by AAVs to rescue gastric symptoms in mice, and emphasizes that peripheral neurons are a worthwhile target for treating [Parkinson’s disease], in addition to the brain.”

Overall, the researchers said, “[O]ur findings suggest that age-related declines in protein homeostasis, including diminished GCase function, may promote susceptibility to [disease causing alpha-synuclein] in the ENS and support the gut-to-brain hypothesis of [the biology of] synucleinopathy.”

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APOE Gene Variants Alter Alpha-synuclein Dynamics, Could Affect Dementia Occurrence in Parkinson’s, Study Suggests

APOE Gene Variants

Genetic variations in the gene apolipoprotein E (APOE) alter the dynamics of alpha-synuclein protein buildup in the brains of mice with Parkinson’s disease (PD), according to a new study. This suggests suggests that alterations in APOE could affect the occurrence of dementia in humans with the neurodegenerative disease, the researchers said.

Titled “APOE genotype regulates pathology and disease progression in synucleinopathy,” the study was published in Science Translational Medicine.

As many as 80% of people with PD will develop dementia — a group of symptoms affecting memory, thinking and social abilities — within two decades of being diagnosed. Nonetheless, the occurrence of dementia in Parkinson’s varies greatly person-to-person: “Many patients take years to develop dementia, whereas others have a more rapid course, and in some cases, dementia precedes motor symptoms,” the researchers said.

Parkinson’s is associated with the formation of toxic protein aggregates, or clumps, in the brain — particularly involving the protein alpha-synuclein. Alzheimer’s disease also is characterized by the accumulation of toxic protein aggregates in the brain, though the exact proteins involved are somewhat different.

The gene APOE encodes a protein of the same name, which helps form molecules called lipoproteins, which are responsible for packaging cholesterol and other fats and carrying them through the bloodstream.

A variant in this gene, called E4, is associated with a significantly increased risk of Alzheimer’s. APOE variants are known to affect how certain Alzheimer’s-associated proteins clump together in the brain. However, whether these variants also affect alpha-synuclein aggregation hasn’t been clear, nor has been the effect of variants in APOE on dementia in Parkinson’s.

Now, researchers at Washington University School of Medicine in St. Louis are trying to bridge this knowledge gap. Using mice with a form of alpha-synuclein prone to aggregation, the scientists engineered mice with one of three genetic variants in APOE — E2, E3, or E4 — or no APOE gene at all, called a knockout. They then compared alpha-synuclein in the brains of these mice.

Using multiple molecular assays, the researchers demonstrated that alpha-synuclein levels were significantly lower in mice with the E2 variant than in mice with the E4 variant or knockout mice. Animals with the E3 variant had alpha-synuclein levels in between these two extremes, though differences were generally not statistically significant in either direction.

Motor function and survival patterns followed trends consistent with this finding: E2 mice had higher motor scores, followed by E3, then E4, and knockout. Similarly, E2 mice survived significantly longer (median 18.4 months) than E4 (11.7 months) or knockout mice (11.6 months), with E3 mice in between the extremes (median 12.7 months).

These data suggest that APOE genetic variants affect the dynamics of alpha-synuclein in the brain.

“What really stood out is how much less affected the APOE2 mice were than the others,” Albert (Gus) Davis, MD, PhD, a professor at Washington University School of Medicine and the study’s lead author, said in a press release.

“It actually may have a protective effect, and we are investigating this now,” Davis said. “If we do find that APOE2 is protective, we might be able to use that information to design therapies to reduce the risk of dementia.”

The team then looked for connections between APOE variants and dementia in people with Parkinson’s.

First, the researchers assessed two groups of PD patients who had been followed for several years: one from the Parkinson’s Progression Markers Initiative, involving 251 people, and the other, which includes 170 people, from the Washington University Movement Disorders Center. In both groups, individuals with the E4 variant had significantly faster rates of decline in cognitive scores as compared with those with other variants. Importantly, this effect remained significant after adjustment for other factors known to affect cognitive decline, including the presence of neurotoxic proteins in the fluid around the brain, and educational attainment.

Additionally, in a separate group — the NeuroGenetics Research Consortium, numbering 1,030 people, in which cognitive scores were measured at only one time point — the E4 variant was associated with significantly lower cognitive scores at the time of assessment, and with the onset of cognitive difficulties at a younger age.

“Together, these data corroborate the finding that APOE ε4 is associated with cognitive impairment and a faster rate of cognitive decline in PD,” the researchers said.

Because this effect was independent of other toxic brain proteins, the team concluded this most likely was a consequence of increased alpha-synuclein in the brain, as evidenced by the data in mice.

All in all, these findings implicate APOE in the molecular progression of Parkinson’s and, specifically, the onset of dementia. Thus, APOE or related proteins in the brain might be a viable therapeutic target for treating dementia in Parkinson’s, the researchers said. Further studies will be needed to test this idea.

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Cannabinoids Ease Motor Symptoms in Mouse Model of Parkinson’s, Early Results Show


Cannabinoid-based formulations in development at GB Sciences were able to ease behavioral symptoms linked to the loss of dopamine producing-nerve cells — a hallmark of Parkinson’s — in a mouse model of the disease, the company said.

GB Sciences will use these early results to support an Investigational New Drug Application it plans to file with the U.S. Food and Drug Administration, requesting to open a clinical trial later this year.

“These positive preclinical results suggest that our cannabinoid-containing complex mixtures may be useful for the treatment of Parkinson’s disease symptomology,” Michael Farley, president and director of GBS Global Biopharma, said in a press release.

Results to date are part of the study’s midterm report, the company said, and the study is continuing.

Parkinson’s is characterized by the degeneration and death of a specific group of nerve cells — called dopaminergic neurons — in the substantia nigra, a brain region that regulates muscle movement and coordination. These cells are responsible for the production of dopamine, a critical brain chemical, or neurotransmitter, that regulates brain cell activity and function.

Cannabinoids are the active chemicals that give the cannabis plant its medical and recreational properties. Numerous studies have looked at the chemicals’ potential to ease motor symptoms in several neurodegenerative conditions, including Parkinson’s.

GB Sciences is creating a pipeline of novel medicines based on the company’s patent-pending formulations of chemicals extracted from the cannabis plant.

Results of the preclinical study, led by Lee Ellis of Canada’s National Research Council (NRC), showed that several of GB’s cannabinoid formulations eased behavioral symptoms in a mouse model of Parkinson’s. One formulation completely relieved the symptoms, without signs of significant side effects.

“Several of GB Sciences’ mixtures were effective,” said Andrea Small-Howard, chief science officer and director of both GB Sciences and GBS Global Biopharma. “In fact, our most effective mixture was able to ‘rescue’ the PD-like behavioral changes to the point where the treated animal’s behavior was back to baseline. In addition, our PD formulas produced negligible side effects, which is equally important.”

The next and final phase of this ongoing study will look into the mechanisms underlying these formulations and the benefits seen. Researchers suggest that the cannabinoids either protect dopamine-producing neurons from dying, or enhance the production of dopamine by surviving neurons.

All results will be used to support the company’s request to the FDA.

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Mouse Study Implicates Calcium Channel in Neuronal Death in Parkinson’s Disease

mouse study, Parkinson's

A calcium channel called Cav2.3 plays a role in neuronal death, and may be a useful therapeutic target in Parkinson’s disease, suggests a new study done primarily in mice.

The study, titled “Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease,” was published in Nature Communications.

Motor symptoms in Parkinson’s disease are caused primarily by the death of dopamine-producing (dopaminergic) neurons in a part of the brain called the substantia nigra (SN). It has been well-established that calcium signaling — that is, calcium ions moving in or out (but usually in) of a cell, which is mediated by specialized “channel” proteins — plays an important role in the functioning and survival of these neurons, but the precise mechanisms are still not fully understood.

In the new study, researchers began by measuring the levels of several different calcium channels in these neurons in the brains of mice. They were surprised to find higher levels of Cav2.3 than any other calcium channel; Cav2.3 has never been linked to neurodegeneration (neuron cell death) before.

The researchers then used mice that had been genetically engineered so they could not make Cav2.3 and treated them with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a chemical that is toxic to neurons and is “the standard model for preclinical testing of neuroprotective Parkinson’s disease therapies in animals,” the researchers wrote.

In wild-type (i.e. with functional Cav2.3) mice, MPTP treatment resulted in the death of about 40% of the dopaminergic neurons in the substantia nigra.

“In stark contrast, we observed no loss of SN dopaminergic neurons in Cav2.3 knockout animals after MPTP treatment,” the researchers wrote. “Taken together, these data identify Cav2.3 as mediator of SN dopaminergic neuron vulnerability to a degenerative stressor.”

The researchers then measured levels of other calcium-related proteins in neurons lacking Cav2.3, in order to identify possible mechanisms for this phenomenon. They found that these cells had increased levels (by about 40%) of a calcium-sensing protein called NCS-1, and they hypothesized that higher levels of this protein might lend the neurons protection from MPTP.

To test this, the researchers treated mice that lacked NCS-1 with MPTP, which resulted in the death of about 60% of the dopaminergic neurons in the SN — significantly more than was seen in wild-type mice.

“NCS-1 thus emerges as protective factor during SN dopaminergic degeneration, of likely relevance to Parkinson’s disease,” the researchers wrote.

Finally, the researchers turned to human cells. They took skin cells from volunteers, and engineered these into a type of stem cell called induced pluripotent stem cells (iPSCs), which were subsequently induced to differentiate into neurons.

The researchers compared iPSC-derived neurons from people without Parkinson’s disease to those of a Parkinson’s disease patient who had a mutation in the GBA gene (such mutations are associated with a high risk of Parkinson’s disease).

No significant differences were found in the amount of Cav2.3 protein; however, levels of NCS-1 were about 40% lower in the neurons from the person with Parkinson’s. Although this does not provide definitive proof, it suggests that similar molecular mechanisms might be at play in human Parkinson’s disease.

“Collectively, our data strongly suggest opposing roles for Cav2.3 and NCS-1 in Parkinson’s disease,” the researchers said, adding that “Cav2.3 is neurodegenerative whereas NCS-1 is protective for SN dopaminergic neurons. Whether this involves any direct functional or molecular interactions between the two proteins must be clarified in future experiments.”

“Cav2.3 and NCS-1 thus emerge as potential targets for neuroprotective therapy,” they added.

Although a recent Phase 3 clinical trial (NCT02168842) using DynaCirc (isradipine) — a medicine used to treat high blood pressure — to block another type of calcium channel, called Cav1.3, showed that it did not protect against Parkinson’s disease, the authors believe that the therapeutic dose given may not have been sufficient to fully inihibit this channel in dopaminergic neurons. Alternatively, inhibiting this specific type of calcium channel may “be protective only under distinct conditions, e.g. before motor symptoms manifest, or in response to transiently elevated dopamine levels during dopamine replacement therapy,” they added.

Currently, the only available Cav2.3 inhibitor (SNX-482) is not suitable to be used in a clinical setting “due to off target effects.” As such, the “development of high affinity, brain-permeable, and selective Cav2.3 channel blockers is warranted,” the researchers said.

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Study Will Test Brain’s Natural ‘Plumbing System’ in Parkinson’s, Alzheimer’s Mice


Parkinson’s UK and Alzheimer’s Research UK have teamed up to help fund a project that will test whether a “waste disposal system” in the brain could be exploited to help in the understanding and treatment of these diseases, Parkinson’s UK announced.

The new project, which is expected to take about three years to complete, will focus specifically on the glymphatic system. This system, which was  discovered only recently, helps to remove waste products from the brain.

The general idea behind the project is that, since both neurological diseases are associated with the abnormal and toxic buildup of “clumps” of protein in the brain (tau for Alzheimer’s and alpha-synuclein for Parkinson’s), activating the glymphatic system could help remove these clumps and, by extension, fight the disease.

“Studying how the glymphatic system affects the clearance of two distinct protein species that both accumulate in the brain and cause neurodegeneration means we’ll be able to understand how best to harness the power of the system. This will hopefully allow us to provide a new therapeutic target for treatment of the conditions,” Ian Harrison, PhD, said in a press release. Harrison, a professor at University College London, will lead the project.

The glymphatic system is a functional waste clearance pathway for the central nervous system (brain and spinal cord); it works as the brain’s unique method to remove waste. It consists of a “plumbing system” that takes advantage of the brain’s blood vessels and pumps cerebral spinal fluid through the brain’s tissue, flushing away waste.

This system is highly active during sleep, clearing away toxins responsible for Parkinson’s and other neurological disorders.

Using mouse models, Harrison and other researchers will track how tau and alpha-synuclein spread in the brain after the glymphatic system’s activity has been altered (either diminished or increased). It also will determine the effect this change has on mouse behaviors that are related to neurological diseases, such as memory and movement capabilities.

Previous research has suggested that sleep, exercise and low levels of alcohol could help activate the glymphatic system. The new project will build on these findings; researchers also will investigate potential new therapies to target this system.

“This is the first time we’ll be studying the glymphatic system’s role in clearing toxic proteins, and the potential it provides for developing new treatments which are urgently needed by people living with Parkinson’s,” said David Dexter, PhD, deputy director of research at Parkinson’s UK.

Sara Imarisio, PhD, the head of research at at Alzheimer’s Research UK, added: “The causes of Alzheimer’s disease are complex. While there are many differences between Parkinson’s and Alzheimer’s, common biology between both diseases means that research into one condition can provide important insights into the other. This new research could shed light on a disease process that holds potential as a target for future drugs, and that could change the course of Alzheimer’s and other neurodegenerative diseases.”

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New Agent CM101 Could Potentially Treat Parkinson’s, Other Neurodegenerative Diseases, Mouse Study Shows

CM101, brain toxins

A newly developed compound called CM101 helps to clear toxic proteins in the brains of mice, and could be a viable avenue for the treatment of some neurodegenerative diseases, including Parkinson’s disease, researchers say.

This finding was recently presented at the annual meeting of the Society of Neuroscience, in a presentation titled, “Multi-kinase inhibition may have optimal effects on neurodegenerative pathologies via the tyrosine kinase discoidin domain receptors (DDRs).”

Many neurodegenerative diseases are characterized by the buildup of toxic proteins in the brain — for instance, alpha-synuclein in Parkinson’s disease and tau and amyloid-beta in Alzheimer’s disease.

Researchers have been looking for ways to induce neurons (brain cells) to turn on processes that help them clear unneeded proteins, which may help remove these toxic molecules. In a press release, Charbel Moussa, PhD, an associate professor of neurology at Georgetown University and senior author of the study, described this as turning on the “garbage disposal” in neurons.

Researchers had previously investigated tyrosine kinase (TK) inhibitors as a way to do this. TKs play many roles in normal cell functioning; for instance, they are critical in helping cells divide — which is why TK inhibitors, used at high doses, have been developed as treatments for some cancers.

“The idea with these frequent high doses is that controlling cell division or proliferation while keeping the garbage disposal working overtime will incinerate cells that are rapidly dividing. These cancer cells will cannibalize themselves,” said Alan Fowler, a PhD student at Georgetown and study co-investigator.

In experimenting with some of these cancer agents — namely Tasigna (nilotinib) and Bosulif (bosutinib) — the researchers determined that inhibiting the tyrosine kinases called discoidin domain receptors 1 and 2 (DDR1 and DDR2, or collectively, just DDRs) might be the best way to turn on the garbage disposal in brain cells affected by neurodegeneration.

Based on these findings, they synthesized a new compound, CM101 (also known as BK40143), which specifically inhibits DDRs. Initial experiments in mouse models of neurodegenerative diseases have lent validity to CM101 as a potential therapy for these conditions.

“This agent has undergone extensive testing in several animal models of neurodegeneration, and it represents a good candidate that should be investigated in first-in-human trials. We have so far shown that this agent has a superior efficacy to clear neurotoxic proteins in animals compared to similar agents, and we identified DDRs as a preferential and optimal drug target. The next step is to investigate drug toxicity in order to obtain regulatory permission for human application,” Moussa said.

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High Corticosterone Levels a Risk Factor for Parkinson’s, Mouse Study Finds

corticosterone mouse study

High levels of corticosterone — a hormone that regulates energy, immune, and stress responses — is a risk factor for the development and progression of Parkinson’s disease, according to a mouse study.

The study, “Chronic corticosterone aggravates behavioural and neuronal symptomatology in a mouse model of alpha-synuclein pathology,” was published in the journal Neurobiology of Aging.

Parkinson’s disease is a neurodegenerative disorder mainly resulting from the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for controlling body movements.

This is a consequence of overproduction and misfolding of the protein alpha-synuclein in neurons, which leads to the formation of small toxic deposits called Lewy bodies that gradually damage and kill nerve cells. Growing evidence has demonstrated that these alpha-synuclein aggregates are associated with Parkinson’s onset and progression.

“Injection of alpha-synuclein preformed fibrils (PFFs) in different brain regions … induces pronounced alpha-synuclein pathology [aggregate] propagation. Interestingly, in these [mouse] models the amygdala is among the brain regions most severely affected by alpha-synuclein pathology [disease],” the researchers wrote.

The amygdala is an area of the brain involved in memory, decision-making, and emotional responses. Several non-motor symptoms in Parkinson’s, including anxiety and depression, have been linked to structural alterations and functional impairments of the amygdala.

“Similarly, chronic stress and glucocorticoid [imbalance] change amygdala physiology [function], and indeed are involved in the development of anxiety and depression,” they wrote.

The group of researchers from the Brain Mind Institute at the École Polytechnique Fédérale de Lausanne in Switzerland set out to investigate if mood/emotional alterations linked to amygdala dysfunction might accelerate the formation and propagation of alpha-synuclein aggregates associated with Parkinson’s in a mouse model of the disease.

To test their hypothesis, they first treated mice with corticosterone, a glucocorticoid that is normally produced in response to stress, to mimic the effects of depression and chronic stress in the amygdala.

Animals were then injected on one side of the brain’s striatum — a region involved in motor and cognitive control — with either alpha-synuclein preformed fibrils to trigger the formation and propagation of alpha-synuclein aggregates across the whole brain, or with a saline solution (vehicle control).

Chronic treatment with corticosterone triggered depression in animals and had a strong effect on their body shape, fat deposition, body weight, and drinking and eating habits. Injection of alpha-synuclein preformed fibrils had no effects on any of these parameters.

Behavioral tests performed one to two months after the injection of alpha-synuclein showed that animals that had been injected with these fibrils displayed mild anxiety, which was reversed by corticosterone treatment.

However, they found that chronic treatment with corticosterone in animals that had been injected with preformed fibrils led to the accumulation of phosphorylated alpha-synuclein in specific regions of the brain, including the entorhinal cortex, a region involved in memory, spatial navigation, and time perception.

Alpha-synuclein phosphorylation is a chemical modification in which a phosphate group is added to the protein. It is known to occur in Parkinson’s disease, and is thought to be a critical step in disease progression, as it enhances alpha-synuclein’s toxicity, possibly by increasing the formation of aggregates.

They also discovered that treatment with corticosterone in mice that had been injected with alpha-synuclein fibrils increased the loss of dopaminergic neurons.

“We report aggravated alpha-synuclein pathology [disease] and neurodegeneration in mice injected with alpha-synuclein [preformed fibrils] in a condition of heightened corticosterone, suggesting heightened glucocorticoid levels as a risk factor for the development of the neuropathological hallmarks of Parkinson’s disease and potential target for treatment,” the researchers wrote.

“Further studies aimed at elucidating the vulnerability factors of specific brain regions to alpha-synuclein pathology, and why at some point resilience fails and neurodegeneration (such as in the substantia nigra) occurs, are needed and will greatly enhance our understanding of the role of alpha-synuclein pathology in the [development] of Parkinson’s disease and synucleinopathies,” they added.

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Caffeine Plus Coffee Compound Linked to Serotonin Help Protect Brain from Toxic Damage, Mouse Study Says

coffee and its compounds

Two compounds found in coffee — caffeine and EHT, a fatty acid molecule derived from serotonin — work together to protect the brain from damage induced by alpha-synuclein, a study in mice reported.

The study, “Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson’s disease and DLB,” was published in PNAS.

Parkinson’s disease is characterized by alpha-synuclein aggregates. When this protein clumps, it gives rise to small fibrils that accumulate inside brain cells, producing small inclusions called Lewy bodies. These structures are highly toxic and often cause irreparable damage to affected nerve cells, slowly killing them.

Previous studies have shown that alpha-synuclein is abnormally hyperphosphorylated — a chemical modification in which a phosphate group is added to the protein — in the brain of patients with Parkinson’s. This is caused by the lack of activity of the protein phosphatase 2A (PP2A), an enzyme responsible for removing phosphate groups from alpha-synuclein.

Of note, alpha-synuclein phosphorylation is known to occur in Parkinson’s disease, and is thought to be a critical step in disease progression as it enhances alpha-synuclein’s toxicity —possibly by increasing the formation of alpha synuclein aggregates.

Interestingly, studies also report that Eicosanoyl-5-hydroxytryptamide or EHT — a fatty acid molecule found in coffee — promotes the activation of PP2A. In transgenic (or genetically engineered) mice, it was able to reverse the symptoms of phosphorylation to produce large quantities of alpha-synuclein.

The chemical serotonin, a neurotransmitter, is known to serve as a “feel-good” chemical in the brain, influencing a person’s sense of well-being and happiness.

“Considering epidemiologic and experimental evidence suggesting protective effects of CAF [caffeine] in PD [Parkinson’s disease], we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of [alpha]-synucleinopathy,” the researchers wrote.  “[A]mong patients with early PD, the amount of CAF consumption does not impact the rate of progression of the disease, and decaffeinated coffee has been found to be protective in Drosophila models of PD, raising some question about the protective effect of only CAF among the numerous other compounds in coffee.”

Researchers treated alpha-synuclein transgenic mice (SynTg) — which overexpress alpha-synuclein in nerve cells — with either higher doses of caffeine and EHT separately, or with lower doses of both compounds for six months.

SynTg mice treated with caffeine and EHT had lesser accumulation of hyperphosphorylated alpha-synuclein in the brain, which was linked to higher levels of active PP2. These animals also  maintained neuron integrity and function, had lower brain inflammation, and performed better on behavioral tests.

Investigators found the same therapeutic benefits when they used the combined treatment in another mouse model of alpha-synucleinopathy, in which animals were injected with pre-formed fibrils of alpha-synuclein (alpha-Syn PFF).

In both animal models, however treatment with either caffeine or EHT alone failed to produce the same positive effects.

“These findings suggest that these two components of coffee have synergistic effects in protecting the brain against [alpha]-synuclein−mediated toxicity through maintenance of PP2A in an active state,” the researchers wrote.

“As we begin to unravel the polypharmacology of the micronutrients in commonly consumed botanical extracts such as coffee, it seems likely that it will be possible to optimize their composition to enhance efficacy so as to provide widely available, inexpensive, and effective therapeutics for the prevention and treatment of neurodegenerative diseases such as PD, DLB [dementia with Lewy bodies], PSP [progressive supranuclear palsy], and AD [Alzheimer’s disease],” they concluded.

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Inhibiting USP13 Enzyme Can Help Destroy Toxic Alpha-Synuclein Clumps, Mouse Study Finds

USP13 parkin alpha-synuclein

Inhibiting an enzyme called USP13 may represent an attractive therapeutic target for Parkinson’s and other neurodegenerative diseases, preclinical data suggests.

These findings also could hold important implications for a therapy currently being developed to treat Parkinson’s disease — nilotinib.

The study, “Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies,” was published in Human Molecular Genetics.

USP13 belongs to a large family of enzymes called de-ubiquitinases known for their ability to cut chains of a small protein known as ubiquitin that is present inside stress-induced clumps of proteins and other molecules.

Ubiquitination is like a cellular tagging system: By adding an ubiquitin molecule to a protein, it marks it for degradation.

Previous research has shown that USP13 and another similar enzyme called USP5 are important in helping to dismantle clumps of molecules that form when cells are stressed by external factors, called “stress granules.”

Now Georgetown University Medical Center researchers have found that one reason clumps of alpha-synuclein, known as Lewy bodies, develop and accumulate in the brain is that USP13 removes all the “tags” placed on alpha-synuclein that mark it for destruction, or ubiquitination. Toxic aggregates of alpha-synuclein accumulate and are not efficiently cleared.

Researchers analyzed brain tissue samples collected postmortem from 11 patients with Parkinson’s disease. USP13 levels were about 3.5 times higher than samples from subjects not affected by Parkinson’s.

To better understand the role of USP13, researchers used a genetic approach to either increase or decrease the levels of USP13 in mouse neurons cultured in a laboratory dish. These neurons expressed high levels of alpha-synuclein.

The presence of alpha-synuclein alone significantly increased the levels of parkin ubiquitination. Parkin is a protein often found mutated in some Parkinson’s patients.

The team had previously shown that an increase in parkin ubiquitination led to clearance of neurotoxic proteins, including alpha-synuclein, in several animal models of neurodegeneration.

However, expression of high levels of USP13 and alpha-synuclein together significantly reduced parkin ubiquitination, suggesting that USP13 can modulate parkin response.

“Taken together, these data suggest that USP13 may regulate parkin ubiquitination/de-ubiquination cycle,” the researchers wrote.

Additional experiments revealed that decreasing the levels of USP13 increased alpha-synuclein ubiquitination and destruction.

Knocking out the USP13 gene in a mouse model of Parkinson’s disease was able to prevent alpha-synuclein-induced death of dopamine-producing brain cells. Also, genetic inhibition of USP13 led to significant improvement in animals’ motor performance, while improving the clearance of alpa-synuclein toxic molecules.

Importantly, researchers found that a new therapy being studied to treat Parkinson’s disease, nilotinib, worked better when USP13 was inhibited.

Results from a recent Phase 2 clinical trial (NCT02954978) conducted by Novartis showed that nilotinib can modulate dopamine levels and metabolism, as well as prevent the formation of toxic alpha-synuclein aggregates.

Nilotinib is available under the brand name Tasigna as an approved treatment for certain types of leukemia.

“Our discovery clearly indicates that inhibition of USP13 is a strategic step to activate parkin … to increase toxic protein clearance,” Charbel Moussa, PhD, director of Georgetown University Medical Center Translational Neurotherapeutics Program and senior author of the study, said in a press release. “Our next step is to develop a small molecule inhibitor of USP13 to be used in combination with nilotinib in order to maximize protein clearance in Parkinson’s and other neurodegenerative diseases.”

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