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Researchers Work to Map LRRK2 Cell Interactions for Parkinson’s Clues, Study Says

LRRK2

Researchers characterized the structure and interactions of proteins connected to the leucine-rich repeat kinase 2 (LRRK2) gene, the most common genetic cause of Parkinson’s disease, opening up new avenues for the development of new treatments for the disease.

The study,” Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2,” was published in the journal Structure.

Parkinson’s is characterized by the loss of neurons in a region of the brain called the substantia nigra. These neurons produce dopamine, a neurotransmitter, or chemical messenger, that allows brain cells to communicate. Damage and loss to these neurons leads to lower dopamine levels and the characteristic symptoms of the disease.

“The only treatment for Parkinson’s disease in the last 20 years has been dopamine replacement therapy,” which is “not completely effective and can wear off over time,” Amir Khan, associate professor at the School of Biochemistry and Immunology at Trinity College in Dublin and senior author of the study, said in a press release.

The absence of effective treatments may be due to lack of understanding of how neurons become damaged and die. The study focused on the LRRK2 gene, which provides instructions for the production of an enzyme called leucine-rich repeat kinase 2, also known as dardarin.

Some 10% of Parkinson’s cases have an underlying genetic base, and the most common involved gene is LRRK2. The protein also plays a role in sporadic cases of Parkinson’s.

“In other words, afflicted individuals may not have an LRRK2 mutation, but the enzyme ‘runs amok’ in their neurons anyway,” Khan said. “Inhibitors of this enzyme are now in late clinical trials for treatment of Parkinson’s disease.”

The researchers studied the enzyme and its network of substrates (the molecule upon which an enzyme acts) in the laboratory.

In the cell, LRRK2 is involved in important processes like autophagy (cells’ clean-up system), mitochondria functioning (cells’ powerhouses) and protein processing.

Small proteins known as GTPases are physiological substrates, or targets, of LRRK2. These include so-called Rabs — part of a protein superfamilly called Ras, which are essential to cell growth, differentiation and migration, and trafficking of molecules in and out the cells. These enzymes alternate between an active and inactive state.

Previous findings have “place[d] LRRK2 at the center of a Rab signaling cascade that is key to understanding the molecular pathways that underpin [Parkinson’s disease],” the researchers wrote.

The modification of Rabs by LRRK2 modulates their interaction with different molecules, by promoting the interaction of Rabs with two poorly studied proteins termed RILPL1 (Rab interacting lysosomal protein-like 1) and RILPL2, which have been associated with the regulation of ciliogenesis (the assembly of cilia, cells’ structures that sense and process signals).

The researchers used  X-ray crystallography — a technique that provides information about protein structure — to study the 3-D structure of the complex formed by Rabs and RILPL1 and RIPL2 and understand how LRRK2 can affect the brain and lead to Parkinson’s disease.

“The research allowed us to visualize the 3-D structure of a protein complex that is formed when LRRK2 is overactive,” Khan said. “From these structural studies of proteins, we can understand how LRRK2 is able to impose its profound effects on neurons. We are the first group to report the effects of LRRK2 in 3-D detail using a method called X-ray crystallography.”

“An overactive LRRK2 runs loose in neurons and wreaks havoc on motor and cognitive abilities,” Khan said. “In a way, we are chasing the footprints that LRRK2 leaves in the brain to understand what it does, and find ways to stop it.”

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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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LRRK2 Inhibitors May Benefit Parkinson’s Patients With and Without Genetic Mutation, Study Finds

LRRK2

Inhibiting the activity of LRRK2 kinase — an enzyme whose mutated form is one of the most common genetic causes of Parkinson’s disease — may benefit patients both with and without this disease-related mutation, a study finds.

Molecules that block the activity of the LRRK2 kinase — such as DNL201 and DNL151, both being developed by Denali Therapeutics — are currently being tested in clinical trials.

The results of this study, “LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson’s disease,” were published in Neurobiology of Disease. The research was supported by the Michael J. Fox Foundation.

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are one of the most commonly known genetic causes of Parkinson’s disease. Evidence indicates that in people with idiopathic Parkinson’s, in which the disease has no known cause, the LRRK2 protein is overly active, regardless of the patient’s mutation status — whether or not they have a mutated LRRK2. That overly active protein leads to the malfunctioning of lysosomes, the special compartments within cells that digest and recycle different types of molecules. Lysosomal dysfunction is involved in the formation of  protein aggregates, or clumps, called Lewy bodies, which contribute to Parkinson’s and, therefore, neurodegeneration.

Therapies that can inhibit, or block LRRK2 are currently being tested in human clinical trials. However, it is still unclear whether blocking LRRK2 protein activity in people with idiopathic Parkinson’s can prevent lysosomal dysfunction and consequent neurodegenerative processes.

To learn more, investigators at the University of Pittsburgh now studied post-mortem brain samples, specifically from a motor brain region called the substantia nigra, which is severely damaged in Parkinson’s. The researchers characterized lysosomal abnormalities in the surviving dopaminergic neurons — the main source of dopamine, the loss of which is a hallmark of this disease — of idiopathic Parkinson’s patients.

When compared with healthy controls, Parkinson’s patients had more abnormal lysosomes. These changes occurred during the early stages of lysosomal development, the researchers found.

The team then investigated whether these post-mortem cellular findings could be replicated in an animal model of Parkinson’s. Rats were given two distinct dose regimens of rotenone, a pesticide that inhibits mitochondria, or the “powerhouses” of cells. Blocking mitochondria leads to cellular death and the onset of parkinsonian features.

Nine to 14 daily doses of rotenone reproduced many idiopathic Parkinson’s features, including lysosomal defects. This caused neurodegeneration in the striatum and substantia nigra, two brain areas involved in motor control.

Interestingly, five daily doses of the pesticide weren’t enough to cause cell death, but did increase the accumulation of Parkinson’s-related alpha-synuclein protein and produce changes in lysosomes.

“These data demonstrate that, in rotenone-treated rats, [alpha]-synuclein protein levels rise in the dopaminergic neurons prior to the onset of frank neurodegeneration,” the researchers said.

When overactive LRRK2 was blocked in rotenone-treated rats, the protein’s activity was reduced. That, in turn, improved the overall health of lysosomes and prevented the accumulation of alpha-synuclein. These effects were observed in animals without a genetic predisposition to develop Parkinson’s, suggesting that the LRRK2 kinase inhibitors may be effective beyond LRRK2-mutated patients.

“Our work suggests that drugs that block LRRK2, some of which have entered clinical trials, will be useful for people with typical Parkinson’s disease,” J. Timothy Greenamyre, MD, PhD, the study’s lead author, said in a press release.

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LRRK2 Gene Mutation Protects Against Infection But Increases Parkinson’s Risk Via Inflammation, Study Suggests

LRRK2, inflammation

Although it may be protective against infections, a specific mutation in the LRRK2 gene — the gene linked to most inheritable mutations that can cause Parkinson’s disease — may increase Parkinson’s risk by promoting inflammation in the brain, according to new research.

The study, “Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner,” appeared in the journal Science Translational Medicine.

Mutations in the LRRK2 gene are found in about 2% of people with Parkinson’s, with different studies reporting a greater frequency in women. But a mutated LRRK2 also has been associated with greater risk for two other disorders in which inflammation is a key component: Crohn’s disease (CD), which targets the gut, and leprosy, which affects the peripheral nervous system.

LRRK2 is highly expressed in several types of immune cells, including macrophages and natural killer cells. This suggests it plays a role in innate immunity — nonspecific defense mechanisms prompted by any given microbe.

To test this hypothesis, a team from Canada assessed LRRK2 expression in human white blood cells and tissues during inflammation, and studied viral and bacterial infections in Lrrk2 mutant animals.

First, the team found that neutrophils — immune cells that travel to the site of an infection — were the cell type with the highest expression of LRRK2 in healthy participants. Immune–related tissues, such as the bone marrow and lymph nodes, showed abundant RNA levels of LRRK2. RNA is the genetic template that gives origin to proteins.

Then, the investigators found significant protein production in gut samples of patients with Crohn’s disease, and in brain tissue of people infected by HIV, rabies virus, or virally infected peripheral nerve roots. All of these are characterized by inflammation.

Taking this data together with findings in Parkinson’s patients, which showed strong LRRK2 production in brain white blood cells, the team “concluded that LRRK2 appears to be abundant in infiltrating leukocytes of human tissues during acute or chronic inflammation.”

In mice, the researchers used a sepsis model — inoculation with Salmonella typhimurium — and an encephalitis model, induced by infection with reovirus, to assess the role of LRRK2 in acute bacterial and viral infection.

They found that, in both models, normal (wild-type) Lrrk2 expression was protective compared with complete Lrrk2 absence or production from only one gene copy. Female mice lacking Lrrk2 showed a stronger inflammatory response than male animals that lacked the gene, the researchers noted.

Then, the scientists studied the p.G2019S mutation — the most common mutation in LRRK2 — which increases the activity of the LRRK2 protein. Carrying this mutation enhanced inflammation and boosted the protective effect of normal Lrrk2, with reduced bacterial growth and longer survival during sepsis. This greater protection was mediated by the higher number of myeloid cells — monocytes, macrophages and neutrophils — in the spleen.

In mice with sepsis and with the Lrrk2 mutation, the scientists also observed increased oxidative damage in the spleen and the brain.

“When mice with the Parkinson’s-linked mutation were infected with Salmonella bacteria, we saw very high levels of  in the brain, almost twice as high as in normal mice,” Bojan Shutinoski, PhD, the study’s first author, said in a press release. “This was particularly surprising because the bacteria never even entered their nervous system!”

Mouse pups with encephalitis and no Lrrk2 had increased mortality — especially females — and increased activation of microglia, the resident immune cells of the brain. Animals with the p.G2019S mutation showed reduced survival despite lower viral levels. These mice also exhibited greater brain infiltration of white blood cells, and higher concentrations of the alpha-synuclein protein — the main component of Parkinson’s hallmark Lewy bodies.

The higher mortality in mice with the p.G2019S mutation was likely due to increased enzymatic activity of Lrrk2, as animals with a mutation (p.D1994S) that suppresses this activity showed greater survival.

“Our findings support a growing body of evidence that the LRRK2 protein functions in immune cells both within the brain … and the periphery,” the investigators said.

“Everyone thought that LRRK2’s primary role was in the brain, because of its association with Parkinson’s disease. But our research shows for the first time that its primary role is probably in the immune system,” said Michael Schlossmacher, MD, the study’s senior author and a neurologist at The Ottawa Hospital.

“Our research suggests that certain mutations in LRRK2 enhance inflammation and help the body to defend itself better against viruses and bacteria, but this enhanced inflammation could also increase the risk of Parkinson’s and other brain diseases,” added Schlossmacher, also a professor at the University of Ottawa Brain and Mind Research Institute.

The findings are in line with other additional studies suggesting that Parkinson’s may start outside the brain, and showing a link with Crohn’s disease.

“If this theory about LRRK2 is correct, it could open the door for the monitoring of infections as a key risk element for prediction, early detection and prevention of Parkinson’s, and importantly, for new treatment approaches in general,” Schlossmacher said.

The results also may have implications for the clinical development of therapies that block LRRK2 activity.

“Our research suggests that these drugs may well succeed in safely reducing excessive inflammation,” Shutinoski said. “However, we should be careful not to abolish LRRK2 function altogether, as this could make people more susceptible to infections, in particular when being treated potentially for years.”

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Centogene Launches 2-Year Global ROPAD Study to Assess the Genetics of Parkinson’s Disease

ROPAD study, Parkinson's genetics

A two-year, global, observational study that will assess the contribution of genetic factors in the development of Parkinson’s disease has been launched by Centogene, in collaboration with the University of Lübeck.

The new study (NCT03866603), which is called “Rostock International Parkinson’s Disease Study” or ROPAD, seeks to enroll around 10,000 participants worldwide to get a representative snapshot of the genetic variability in a large population of patients with this progressive neurodegenerative disease.

Adult individuals, 18 or older, who have been clinically diagnosed with Parkinson’s disease are eligible to participate in the study, as well as individuals who are family members of a patient with LRRK2 parkinsonism or are at high risk of having the disease.

The main goal of the study is to pinpoint the specific genetic mutations and genes that may be associated with the development of Parkinson’s disease.

The study’s primary outcome will be to assess the number of patients carrying mutations in the LRRK2 gene, in which more than 100 different mutations associated with late-onset Parkinson’s disease have already been identified. The researchers will also assess, as the study’s secondary outcomes, the prevalence of mutations in other genes previously linked to Parkinson’s, such as GBA.

All the genetic analysis will be performed using the CentoCard, Centogene’s proprietary, CE-marked device that has been designed to collect and evaluate dried blood spot samples.

“Centogene is committed to bringing hope to patients and their families by shortening the diagnostic odyssey, and we are proud to be working on this important study that may have vast implications for the future diagnosis and treatment of Parkinson’s disease,” Arndt Rolfs, CEO and founder of Centogene, said in a press release.

“All too often clinical studies do not reflect the ethnic diversity of the world, and this study is unique in that we are working across all ethnicities worldwide and crosschecking the effect of environmental components and individual genetics. We are excited about the contribution that Centogene and our partners are making in discovering deeper insights into Parkinson’s disease genetics,” Rolfs added.

Patients carrying genetic mutations linked to the development of Parkinson’s disease will have the opportunity to participate in the “LRRK2 International Parkinson’s Disease Project (LIPAD),” a study led by professor Christine Klein at the University of Lübeck which is designed to document the frequency of all signs and symptoms of Parkinson’s disease among this particular population.

In addition, patients participating in ROPAD who are carriers of LRRK2 mutations will have the chance to enroll in future clinical studies led by Denali Therapeutics, Centogene’s study partner, which is currently working on a set of new investigational therapies for neurodegenerative disorders.

To know more about the ROPAD trial and how to participate, visit Centogen’s webpage or its ClinicalTrial.gov registry page.

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Natural Variant of Vitamin B12 Can Prevent Neurodegeneration in Parkinson’s Preclinical Models

vitamin B12 AdoCbl 5’-deoxyadenosylcobalamin

An active form of vitamin B12 can reduce the effects of dopamine loss in Parkinson’s disease caused by genetic mutations in the LRRK2 gene, a study suggests.

These finding means that this form of vitamin B12 could be used as the basis for developing new therapies for treating Parkinson’s.

The study, “Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection,” was published in Cell Research.

Several studies have shown that overactivation of the LRRK2 enzyme, due to genetic mutations in the LRRK2 gene, is associated with the development of a hereditary form of Parkinson’s disease. But increasing evidence has suggested that this enzyme also may contribute to the progression of sporadic cases of Parkinson’s — ones caused by environmental factors.

Increased activity of the LRRK2 enzyme contributes to the accumulation of toxic alpha-synuclein fibers in dopamine-producing neurons of the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in Parkinson’s disease.

Given its important role, researchers have focused on finding ways to prevent the activity of this enzyme as a strategy for treating this neurodegenerative disorder.

Now, an international team of researchers has found that one natural variant of vitamin B12, called AdoCbl (5’-deoxyadenosylcobalamin), can effectively regulate the activity of the LRRK2 enzyme. AdoCbl is approved by the U.S. Food and Drug Administration.

When tested in experimental cell line models, the team found that AdoCbl could significantly reduce the enzyme’s activity, even when it was genetically modified to carry the G2019S mutation — the most common LRRK2 variant linked to Parkinson’s.

Further analysis confirmed that AdoCbl had the ability to directly bind to LRRK2, changing its three-dimensional structure, and preventing its normal function. This allows AdoCbl to work as a strong inhibitor of the enzyme.

“AdoCbl represents a starting point for the development of a new class of LRRK2 activity modulators for the much-needed treatment of LRRK2-linked pathological conditions such as Parkinson’s disease,” the researchers said.

To explore AdoCbl’s therapeutic potential, the team next administrated it in worms carrying the G2019S mutation. The experiments revealed that AdoCbl treatment could prevent the death of dopamine-producing nerve cells and prevent the manifestation of symptoms associated with neurodegeneration.

Additional analysis also revealed that AdoCbl could prevent neurotoxicity and dopamine deficits in fly and mouse models carrying different LRRK2 mutations associated with Parkinson’s.

Identification of vitamin B12 as a modulator of LRRK2 activity “constitutes a huge step forward because it is a neuroprotective vitamin in animal models and has a mechanism unlike that of currently existing inhibitors,” Iban Ubarretxena, director of the Biofisika Institute and co-author of the study, said in a press release.  Biofisika is  a joint research center of the University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea).

“[This active form of vitamin B12] could be used as a basis to develop new therapies to combat hereditary Parkinson’s associated with pathogenic variants of the LRRK2 enzyme,” he added.

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Next 20 Years Expected to Bring ‘Message of Hope’ to Parkinson’s Patients, Review Study Finds

hope and Parkinson's

Discoveries into molecular mechanisms, risk factors — especially genetic — and advances in potential and repurposed therapies for Parkinson’s disease over the last 20 years are reason to believe that major breakthroughs await the next two decades, a review article by two researchers states.

The review article, “Therapies to Slow, Stop, or Reverse Parkinson’s Disease” was published in a supplement of the Journal of Parkinson’s Disease.

The development of better laboratory models, especially animal models that capture the slowly progressive nature of Parkinson’s, together with data resulting from scientific research and early clinical trials “strongly justifies sending this message of hope,” the authors write, explaining that the mechanisms underlying this neurodegenerative disease are gradually being deciphered.

The researchers, Tom Foltynie at University College London and J. William Langston at Stanford University, highlighted possible therapies that are most likely to emerge as disease-modifying treatments for Parkinson’s, despite the considerable challenges that remain in bringing a treatment successfully through a clinical study.

Based on the knowledge that mutations in the LRRK2 gene are one of the most common genetic causes of Parkinson’s disease, researchers have focused on therapies that can inhibit (block) LRRK2. But these efforts have been hindered by lung complications (lung toxicity) in primates exposed to inhibitor candidates, and scientists are exploring more selective ways of delivering such medications to avoid toxicity.

Questions also remain as to whether the brain is the prime target for LRRK2 activity, with some evidence pointing to the gut as well.

Treatments targeting the GBA gene, which encodes an enzyme called beta-glucocerebrosidase, may be relevant for people with sporadic forms of the disease in whom low levels of beta-glucocerebrosidase have been observed. This enzyme plays an important role in the mobilization and processing of alpha synuclein, which is low in GBA mutation carriers.

Ambroxol, an approved treatment for respiratory diseases associated with sticky or excessive mucus, is known to boost beta-glucocerebrosidase activity. However, it remains to be determined if Parkinson’s patients can tolerate the dose required for this therapy to reach the central nervous system. Other molecules that work in the body in ways similar to Ambroxol have been identified.

Since most available Parkinson’s therapies aim to ease motor symptoms, targeting non-motor features like cognition, speech, gait, balance difficulties and autonomic failure (or problems with regulating blood pressure and other process controlled by the autonomic nervous system) is important, given that many of these may precede motor onset. This could allow treatments to be started earlier, possibly delaying or preventing the onset of motor symptoms.

One approach to slowing disease progression gaining interest is that of “repurposing” medications already approved for diseases other than Parkinson’s. Preclinical studies found that type 2 diabetes medications — scientifically known as glucagon-like peptide 1 (GLP-1) receptor agonists — protect against alpha-synuclein-induced neurodegeneration. Various ongoing Phase 2 trials are assessing the effect of various GLP-1 receptor agonists (liraglutide, lixisenatide and semaglutide ) in Parkinson’s disease patients — NCT03659682NCT03439943NCT02953665). Plans for a Phase 3 trial of exenatide, another GLP-1 agonist, are underway.

Medicines used to treat primary biliary cirrhosis (an autoimmune disease of the liver; ursodeoxycholic acid), chronic myelocytic leukemia (nilotinib) and asthma (salbutamol and clenbuterol) also hold promise for Parkinson’s as they seem to contribute to nerve cell survival, eliminate toxic alpha-synuclein buildup, and modulate alpha-synuclein production, respectively.

Various studies have linked alpha-synuclein-induced neuroinflammation to Parkinson’s disease. As such, immunomodulatory therapies can be a treatment option. Evidence suggests a person’s immune system can react to toxic forms of alpha-synuclein and trigger an inflammatory reaction, which can speed disease progression. Azathioprine and sargramostim, both immunomodulatory medications, are being considered as potential candidates for slowing Parkinson’s progression.

A link between metabolism products generated by gut bacteria and brain inflammation has also been identified, and scientists might look to manipulate the gut microbiome — the trillions of microorganisms and their genetic material that live in the intestinal tract — in Parkinson’s patients, study the effects of such manipulation on the neurodegeneration process.

Lastly, the authors highlighted the possible use of nanoparticles in the disease context, as these molecules have been shown to block the formation of toxic alpha-synuclein clusters and actively work against their aggregation. In theory, nanotechnology might hold the potential to accurately target Parkinson’s-related neuropathology.

“We now have better understanding of the processes involved in PD [Parkinson’s disease] degeneration and can therefore have greater confidence that laboratory data and positive results from early clinical trials will ultimately translate to therapies that slow down PD progression,” Foltynie and Langston said in a news release.

“There are currently no drugs that have been proven to slow down PD progression. Demonstrating that one or several of the candidate approaches is successful will lead to a frameshift in patient care,” they added. “Useful cooperation and coordination between investigators around the globe are significantly accelerating the path towards discovering agents that may slow, stop, or even reverse the progression of PD.”

Their review concluded by stressing the possible importance of combination treatments in future clinical trials.

“It is tempting to speculate that the future patient may be recruited into research reminiscent of the current state of play in HIV/cancer fields, e.g., where following genotyping/ microbiome testing, they are either given the curative enzyme corrective therapy or randomised to receive combination therapies rather than any/each of these alone,” they wrote.

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Inflammatory Signals from Non-neuronal Cells Linked to Neurodegeneration in Fly Study

Furin 1

The protein Furin 1, produced by dopaminergic neurons — nerve cells that synthesize the neurotransmitter dopamine — triggers a harmful inflammatory molecular cascade in neighboring non-neuronal cells that contributes to the degradation of these neurons over time, a study in flies found.

Because Furin 1 is controlled by LRRK2 — a major player in neurodegeneration in Parkinson’s disease — the findings begin to reveal how LRRK2 causes the loss of dopaminergic neurons in patients. Blocking this inflammatory signaling protected flies from age-dependent neurodegeneration.

The research, “A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration,” was published in Cell Reports.

Mutations in the LRRK2 gene are one of the most commonly known genetic causes of Parkinson’s disease and 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.

Glial cells — non-neuronal cells that provide support, protection, and nutrition for neurons — help neurons when they are in molecular distress. In certain conditions, glia become overly activated by these “mayday” callings and activate an inflammatory cascade, which contributes to the degradation of the distressed neurons.

Researchers from the Buck Institute for Research on Aging have previously identified Furin 1 as a mediator of LRRK2’s ability to regulate neuronal transmission in Drosophila melanogaster (fruit fly) larvae.

“Working in flies allowed us to identify a vicious cycle: stressed neurons signal to the glia and trigger inflammatory signals in the glia, which become harmful for the neuron as the brain ages. Interestingly, the genetic components of this crosstalk are conserved between flies and humans, boosting our enthusiasm and confidence that future work might lead to novel therapeutic paradigms,” Buck professor Pejmun Haghighi, PhD, senior author of the study, said in a news release.

In this study, investigators sought to test whether Furin 1 responds to LRRK2 in the adult fly brain and whether it is involved in mediating the toxic effect of LRRK2 mutations in dopamine-producing neurons.

The team generated two Parkinson’s disease fly models: one produced too much LRRK2 within neurons; the other had paraquat-induced dopaminergic neurodegeneration.

Paraquat is a toxic, fast-acting herbicide that when fed to flies induces the rapid degradation of dopamine-producing neurons and severely reduces their lifespan.

Fly brain tissue analysis revealed both LRRK2 overexpression and paraquat models had increased Furin 1 protein production in dopaminergic neurons. Furin 1 was found to be regulated by LRRK2 and the trigger of the inflammatory molecular cascade.

“Furin 1 is the real culprit in the interaction between the neurons and glial cells. It’s the ‘finger’ that pushes the switch on the signaling cascade,” said postdoctoral fellow Elie Maksoud, PhD, the study’s lead author.

Furthermore, reducing the amount of Furin 1 within neurons protected against toxicity.

Furin 1 acts on a molecule known as glass bottom boat (Gbb). Gbb binds to bone morphogenetic proteins (BMPs), a family of proteins that promote the formation of bone and the skeleton but are also essential for several neuronal processes. Various forms of these BMPs can be found in the form of molecular receptors in glial cells.

Scientists set up to investigate whether there was a genetic interaction between the overexpression of LRRK2 or Furin 1 and genes associated with BMP molecular pathways.

They reported that furin 1 toxicity was linked to increased BMP signaling in glial cells of both fruit fly models. By genetically silencing Gbb (reducing its production), researchers demonstrated that the action reversed the age-dependent loss of dopaminergic neurons and protected against LRRK2 protein toxicity.

Results suggest that the observed toxicity is mostly initiated by dopamine-producing neurons, which in turn activate BMP-mediated molecular communication with glial cells.

Investigators hypothesize that these supportive non-neuronal cells might send inflammatory signals back to neurons, causing neurodegeneration.

“Furin 1 is a druggable target. Our hope is that treatments can be developed to reduce this toxic crosstalk before it becomes a serious problem for the dopaminergic neurons,” Maksoud said.

Haghighi said, “We have known for some time that different forms of genetic or environmental stress in neurons can trigger a response in glial cells; now we’ve been able to identify a molecular mechanism that explains how neuronal stress can lead to activation of inflammatory signals in glial cells.

“We’re looking at a new way to prevent Parkinson’s, especially in those who have risk factors for the disease. The effects of this toxic signaling are age-dependent, they accumulate over time. The goal is to intervene as early in the disease process as possible.”

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PF-360 Provides Some Benefits But Does Not Improve Dopaminergic Function, Mouse Study Shows

PF-360 mouse study

Treatment with PF-360, an investigational leucine-rich repeat kinase 2 (LRRK2) inhibitor, can efficiently decrease LRRK2’s phosphorylation levels, known to be elevated in Parkinson’s patients, in the brains of a mouse model of Parkinson’s disease, a preclinical study reports.

However, despite some observed dose-dependent therapeutic effects, including gait improvement, no robust changes in dopaminergic function were observed.

Results of the study were recently presented during the Society for Neuroscience’s 2018 conference in San Diego in a poster titled “Assessment of the Anti-parkinsonian Effects of the Potent and Selective LRRK2 Kinase Inhibitor PF-360 in the AAV-A53T Mouse Model of Parkinson’s Disease.”

The study was the result of a collaboration between several institutions including Charles River Discovery, Merck, Pfizer, Atuka Inc., and The Michael J. Fox Foundation for Parkinson’s Research.

The LRRK2 gene provides instructions for making a kinase, which is a protein that regulates the function of other molecules. Mutations in this gene put the protein into an overly activated state.

Mutations in the LRRK2 gene are one of the most commonly known genetic causes of Parkinson’s disease and 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.

Scientists believe that blocking LRRK2’s activity has the potential to slow disease progression.

Using a selective LRRK2 inhibitor called PF-360, researchers studied the dose-response efficacy of the potential therapy in two different mouse models (C57BL/6J and LRRK2-G2019S) that were injected with a “biological cocktail” of an adeno-associated virus combined with a human mutated A53T alpha-synuclein (AAV-A53T) — the major component of protein clumps called Lewy bodies, a hallmark of Parkinson’s.

They used 90 C57BL/6J mice 10-12 weeks old and 105 LRRK2-G2019S mice, 75 of which were 11-12 weeks old and 30 were 5-6 months old. In mouse “time,” 12 weeks is equal to adulthood.

This induced the degeneration of dopaminergic neurons in an area of the brain called the substantia nigra and decreased dopamine and tyrosine hydroxylase — the enzyme responsible for catalyzing levels of L-DOPA, the precursor to dopamine — in the striatum, mimicking Parkinson’s disease.

Mice were treated for 42 days with a diet containing PF-360 or a placebo (control), which was begun seven days prior to AAV-A53T injections.

PF-360 inhibited LRRK2 phosphorylation in the animals’ brain cortex and lungs at a specific site of the protein called serine 935 (serine is an amino acid, or the proteins’ building block). This protein region is required for interaction of LRRK2 with other molecules.

Phosphorylation (the adding of a phosphate group) alters a protein’s structure turning it, for instance, into an activated or deactivated state. As such, phosphorylation is the most common mechanism of regulating protein function and transmitting signals throughout the cell.

Pronounced therapeutic effects were observed with increasing doses (1 mg/kg, 3 mg/kg, 10 mg/kg, 30 mg/kg, and 60 mg/kg of PF-360) in both animal strains and age groups.

AAV-A53T injection led to motor impairments such as decreased speed (longer stride duration, shorter step length), slower swing speed, and reduced hind limb protraction (forward extension).

LRRK2-G2019S mice at 11-12 weeks old recovered their hind limb protraction and retraction with 10 mg/kg of PF-360, while older animals at 5-6 weeks of age had their overall speed (stride duration and swing speeds) improved with 30 mg/kg of the treatment.

No gait changes were observed after 42 days of PF-360 treatment in C57BL/6J mice. However, there was an insignificant treatment-related trend toward increased tyrosine hydroxylase-positive cells in the substantia nigra of C57BL/6J animals.

After treatment, a significantly higher number of tyrosine hydroxylase-positive cells were observed in older LRRK2-G2019S mice.

An increase in tyrosine hydroxylase-positive cells is indicative of an increase in the number of nerve cells that can produce either L-DOPA or dopamine.

Neurochemical analysis revealed that PF-360 delivery to younger animals did not improve striatum levels of dopamine or the intermediate end products of dopamine’s metabolism (3,4-dihydroxyphenylacetic acid and homovanillic acid).

However, treatment significantly increased homovanillic acid levels in older LRRK2-G2019S mice.

Given that most evidence suggests an LRRK2 contribution to Parkinson’s disease via abnormal phosphorylation, this study shows that although PF-360 can reduce LRRK2 phosphorylation levels, both in the brain and in the periphery, it failed to show robust improvements in dopaminergic function.

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Appendix Removal Early in Life Reduces Risk of Developing Parkinson’s, Study Shows

appendix, Parkinson's risk

The healthy human appendix contains Parkinson’s disease-related alpha-synuclein aggregates, and removing the organ early in a person’s life reduces the risk of developing the disease, a study has found.

The study, “The vermiform appendix impacts the risk of developing Parkinson’s disease,” was published in Science Translational Medicine. The work was led by researchers at the Center for Neurodegenerative Science at the Van Andel Research Institute in Michigan.

“Our results point to the appendix as a site of origin for Parkinson’s and provide a path forward for devising new treatment strategies that leverage the gastrointestinal tract’s role in the development of the disease,” Viviane Labrie, PhD, an assistant professor at Van Andel and senior author of the study, said in a press release.

In the brains of Parkinson’s patients, there is a buildup of a protein called alpha-synuclein that forms clumps known as Lewy bodies. These clumps are toxic and lead to neuronal death.

“Gastrointestinal (GI) dysfunction is a common nonmotor symptom of PD [Parkinson’s disease], often preceding the onset of motor symptoms by as many as 20 years,” the researchers wrote.

In addition, it has been shown that neurons innervating the intestines of Parkinson’s patients contain aggregated alpha-synuclein.

“Accumulation of alpha-synuclein in the GI tract not only may contribute to the nonmotor symptoms of PD but also has been hypothesized to contribute to PD pathology in the brain,” the researchers said.

Studies have revealed the existence of many alpha-synuclein aggregates in the appendixes of early-stage and established Parkinson’s patients, as well as in neurologically intact subjects.

The appendix — a worm-like organ that sticks out of the large bowel in the lower right side of the abdomen — helps the immune system detect and eliminate harmful microorganisms, while regulating the gut’s bacterial composition.

In this study, researchers investigated whether this tiny organ contributes to Parkinson’s disease risk.

They analyzed two separate, yet complementary, epidemiological data sets: the nationwide Swedish National Patient Registry (SNPR) and the Parkinson’s Progression Markers Initiative (PPMI).

The SNPR contains information on 1.6 million individuals with a follow-up period of up to 52 years. Investigators identified all individuals who had had an appendectomy (surgical removal of the appendix) from 1964 to 2015 and obtained data on their surgical procedure, year of birth, year of surgical procedure, sex, geographic location (municipality), and, when applicable, date and cause of death. For each patient who underwent an appendectomy, there were two control participants who had not had their appendix removed matched in year of birth, sex, and geographic area.

This data-set analysis revealed that appendix removal was associated with a 19.3% lower risk of developing Parkinson’s than controls. Parkinson’s was diagnosed in 1.17 out of every 1,000 patients who had an appendectomy compared with 1.4 per 1,000 in the general population.

The surgery had the greatest impact on those living in rural areas, with a significant 25.4% reduction in Parkinson’s risk, indicating that removal of the appendix might influence environmental risk factors for the disease. Interestingly, no appendectomy-related benefit was observed in the urban area sample.

“The age of PD diagnosis was, on average, 1.6 years later in individuals who had an appendectomy occurring 20 or more years prior than in cases without an appendectomy. We also observed a significant delay in age of PD onset in individuals with an appendectomy 30 or more years prior, but a limited size in this longer latency group precluded further analysis,” the scientists said.

Researchers then looked at the PPMI data set, which contained detailed information about Parkinson’s diagnosis, age of onset, and other demographic factors, as well as the genetic information of 849 patients.

The team chose to focus on individuals who had their appendix removed at least 30 years before being diagnosed with Parkinson’s, because the early-stage phase of Parkinson’s can last for decades before an accurate diagnosis.

Results showed that age at disease onset was significantly delayed by 3.6 years in those who had undergone an appendectomy (54 individuals, representing 6.4% of the Parkinson’s sample), compared with those who had not.

Disease occurrence was not linked to immune disorders not affecting the gastrointestinal tract, nor was it related to the surgical event itself.

Once a Parkinson’s diagnosis had been established, there were no differences in symptom severity between people with and without a history of appendectomy, suggesting the appendix can potentially impact disease mechanism before the clinical onset of symptoms.

The team then explored the interaction between the appendix and environmental/genetic Parkinson’s risk factors. They reported that the surgical procedure delayed the age of onset in subjects with a family history — meaning those with one or two family members with Parkinson’s — but had no effect in individuals without a family history of the disease.

Importantly, those with a mutation in the LRRK2GBA, or SNCA gene — which are common in hereditary Parkinson’s cases — did not benefit from the appendectomy, indicating that removal of the appendix may be more protective against environmental causes of Parkinson’s rather than genetic ones.

Tissue analysis showed that the mucosa and neurons within the healthy human appendix were filled with aggregated alpha-synuclein. Such accumulation was evident in all age groups, including subjects younger than 20.

Although appendixes of both people with and without Parkinson’s contained disease-prone forms of alpha-synuclein that tend to aggregate rapidly, the Parkinson’s group’s “diseased” protein content was higher than that of the control group.

“We were surprised that pathogenic forms of alpha-synuclein were so pervasive in the appendixes of people both with and without Parkinson’s. It appears that these aggregates — although toxic when in the brain — are quite normal when in the appendix. This clearly suggests their presence alone cannot be the cause of the disease,” Labrie said.

Next, the scientists will search for which appendix-related factor(s) may contribute to Parkinson’s disease.

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