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 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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Loss of Function in Key Genes Doesn’t Change Parkinson’s Risk, Study Finds

LRKK and Parkinson's

Loss or inactivation of a single gene copy of LRRK1 or LRRK2 — LRRK mutations being a common genetic cause of Parkinson’s disease — neither increases the risk nor protects against the disease, a new study showed.

These findings also support the use of kinase inhibitors targeting mutant LRRK2 as a therapeutic option for the disease.

The study, “Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease,” was published in JAMA Neurology.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene — which provides instructions for making a kinase, a type of protein that regulates the functions of many others inside cells — are considered a common genetic cause of Parkinson’s. These LRRK2 mutations typically cause  overactivation of the LRRK2 kinase, leading to increased cell death and disease progression.

Kinase inhibitors  — substances that specifically block this type of enzyme  — have been proposed to treat Parkinson’s disease. However, previous studies in a Parkinson’s mouse model showed that genetic deletion of both LRRK2 gene copies, also known as alleles, together with its homologue (a gene that shares a common ancestral DNA sequence) LRRK1, still resulted in neurodegeneration.

This indicates that Parkinson’s disease can still develop in the absence of LRRK1 and LRRK2  — in other words, in a loss of function (LOF) scenario.

Because LRRK2 inhibitors are being developed as potential Parkinson’s therapies, it is essential to determine whether LOF variants of LRRK1 and LRRK2 could contribute to the risk of developing the disease.

Researchers designed a large case-control study and screened more than 23,000 people  — 11,095 diagnosed with Parkinson’s and 12,615 healthy participants. Using a technique called next-generation sequencing, they analyzed and compared the frequency of LRRK1 and LRRK2 LOF variants in the two groups.

No significant differences were seen between the frequency of LRRK1 (0.205% vs. 0.139%) and LRRK2 (0.117% vs. 0.087%) LOF variants found in patients and healthy controls, suggesting that LOF variants are not directly associated with Parkinson’s disease.
Cell lines derived from those who carried a single copy of several LRRK2 LOF variants had a 50 percent reduction in LRRK2 protein levels when compared with those who carried two normal LRRK2 gene copies.
These findings indicate that neither LRRK1 nor LRRK2 LOF variants increase or decrease the risk of developing Parkinson’s.
“We add more evidence to support the view that LRRK1 is unlikely to cause disease on its own, and more importantly, that pathogenic LRRK2 variants are likely to act through a gain of function rather than an LOF mechanism to cause PD [Parkinson’s disease],” the researchers wrote.
Because LRRK2 LOF variants do not have a negative impact on a person’s health, they consider the use of kinase inhibitors or allele-specific targeting of mutant LRRK2 as viable treatments for Parkinson’s disease.
“Our results support the expansion of these studies in clinical trials and in cells from LRRK2 variant carriers,” they said.

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Source: Parkinson's News Today

Therapies Targeting LRRK2 Gene Could Benefit Broad Population of Parkinson’s Patients, Study Finds

LRRK2 gene

The LRRK2 gene may play an important role in nonhereditary Parkinson’s disease, not just the familial form as previously thought, researchers at the University of Pittsburgh School of Medicine​ have discovered.

“This discovery is extremely consequential for Parkinson’s disease because it suggests that therapies currently being developed for a small group of patients may benefit everybody with the disease,” J. Timothy Greenamyre, MD, PhD, the study’s senior author, said in a press release. Greenamyre is the Love Family Professor of Neurology at Pitt’s School of Medicine, chief of the movement disorders division at the University of Pittsburgh Medical Center, and director of the Pittsburgh Institute for Neurodegenerative Diseases.

These new findings were reported in the study, “LRRK2 activation in idiopathic Parkinson’s disease,” published in Science Translational Medicine.

Parkinson’s disease is a chronic and progressive neurodegenerative condition caused by the loss of dopamine-producing neurons in the substantia nigra, a brain region involved in the control of voluntary movements. It is estimated to affect 1 million people in the U.S. and up to 10 million worldwide.

There are two basic types of Parkinson’s: the familial hereditary form of the disease, which is associated with genetic mutations that make individuals more prone to develop Parkinson’s; and the idiopathic nonhereditary form of the disease, where the causes are unknown.

Genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene — which provides instructions for making a kinase, a type of protein that regulates the function of many others — that cause an overactivation of the protein have been associated with the familial form of Parkinson’s.

However, researchers still do not know if the normal, nonmutated LRRK2 gene could also play a role in the idiopathic form of the disease.

To answer this, investigators set out to analyze the activity of LRRK2 in postmortem brain samples from patients with idiopathic Parkinson’s, who did not have genetic mutations in LRRK2, and healthy individuals from the same age group used as controls.

But studying LRRK2 is difficult because its levels in the brains of Parkinson’s patients are extremely low and hard to detect.

To overcome this, Greenamyre’s team took advantage of a technique called proximity ligation assay, which works by attaching special fluorescent molecules to LRRK2 that glow red when the protein is active, allowing researchers to spot them under a microscope.

Investigators found that LRRK2 activity was increased in dopamine-producing neurons from the substantia nigra of patients with idiopathic Parkinson’s, in comparison with healthy controls.

Interestingly, they observed the same trend in two different rat models of the disease, suggesting that LRRK2 overactivity seems to be important not only for patients with genetic mutations in LRRK2, but also for other individuals with the idiopathic form of the disease.

They then found that LRRK2 activity is linked to alpha-synuclein — a protein that accumulates inside nerve cells, producing small structures called Lewy bodies — that is considered a hallmark of Parkinson’s disease.

Using an animal model of Parkinson’s, they discovered that LRRK2 activation actually blocks the mechanism cells use to clear excessive alpha-synuclein, eventually leading to an abnormal buildup of the protein inside nerve cells.

Researchers then treated these animals with an investigational treatment intended for patients with familial Parkinson’s that works by blocking LRRK2 activity. Remarkably, they observed that the therapy was able to prevent both the accumulation of alpha-synuclein and the formation of Lewy bodies inside nerve cells.

These findings show that, regardless of genetic mutations, the LRKK2 gene plays a role in both types of Parkinson’s disease, indicating that LRRK2 inhibitors may be useful to treat patients with the idiopathic or familial form of the disease.

“We believe that LRRK2 inhibitors may be beneficial not only for the 3 to 4% of people with [Parkinson’s disease] who carry LRRK2 mutations but also for [idiopathic Parkinson’s disease] patients who do not carry LRRK2 mutations,” the authors wrote in the study.

In the future, Greenamyre’s team aims to investigate how LRRK2 overactivity can be prevented, as well as determining the underlying mechanisms that cause its activation in Parkinson’s patients.

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Source: Parkinson's News Today

Mutation Can Trigger Parkinson’s Outside the Brain, Study Finds

Parkinson's outside the brain

The most common gene mutation in Parkinson’s triggers disease outside the brain by changing the body’s immune response to common infections, a study in mice reports.

The research, “Mutant LRRK2 mediates peripheral and central immune responses leading to neurodegeneration in vivo,” was published in the journal Brain.

Parkinson’s patients typically lose dopamine nerve cells in a brain area called substantia nigra, resulting in protein clumps known as Lewy bodies and an increase in brain inflammatory cells. In fact, increasing evidence shows that nerve cell inflammation is key to the development of the disease.

“We know that brain cells called microglia cause the inflammation that ultimately destroys the area of the brain responsible for movement in Parkinson’s,” Dr. Richard J. Smeyne, the study’s senior author, said in a press release. “But it wasn’t clear how a common inherited mutation was involved in that process, and whether the mutation altered microglia.”

Only 10 percent of Parkinson’s cases have a genetic cause. Among these, LRRK2 gene cause the most cases. Mutated LRRK2 is found in 15 to 20 percent of Parkinson’s patients who are Ashkenazi Jews patients and in 40 percent of patients who are North African Arab Berbers.

But the precise link between LRRK2 and Parkinson’s remains poorly understood.

“We know that gene mutation is not enough to cause the disease,” said Dr. Elena Kozina, the study’s first author. “We know that twins who both carry the mutation won’t both necessarily develop Parkinson’s.” Another “initiating event,” or hit, is needed, she said.

Smeyne’s team had already observed that a certain strain of influenza virus predisposed mice to develop disease characteristics that mimic Parkinson’s. This prompted them to wonder if a second hit could come from an infection.

The scientists suspected that LRRK2 mutations could be causing effects outside the brain. To test that idea, they used lipopolysaccharide (LPS) — the major component of the outer shell of gram-negative bacteria — to trigger an immune reaction in the mice.

Neither LPS nor the immune cells it activates are able to cross the blood-brain barrier. This gave the team the perfect tool to test whether inflammation on the periphery affects the brain.

They gave LPS to mice with high levels of the two most common LRRK2 gene mutations. LPS triggered a three to five-fold increase in inflammatory regulators, called cytokines, in these mice, compared with control mice and mice with normal LRRK2.

The cytokines were produced by immune T- and B-cells, two types of white blood cells.

Mice with high levels of cytokines also showed enhanced LRRK2 gene expression in certain immune cells and in activated cells of the brain. This led to nerve cell loss in the substantia nigra, a brain area that plays a critical role in movement.

Nerve cell inflammation in these mice may have been triggered by the ability of circulating cytokines to cross the blood-brain barrier and enter the brain, the team said. This could have created an environment that led to the destruction of the substantia nigra and therefore, movement impairment.

”Overall, this study suggests that peripheral immune signaling plays an unexpected — but important — role in the regulation of neurodegeneration in LRRK2-associated Parkinson’s disease, and provides new targets for interfering with the onset and progression of the disease,” the researchers wrote.

Smeyne cautioned that further research is needed to confirm this link and test it in humans. However, “these findings give us a new way to think about how these mutations could cause Parkinson’s,” he said.

“Although we can’t treat people with immunosuppressants their whole lives to prevent the disease, if this mechanism is confirmed, it’s possible that other interventions could be effective at reducing the chance of developing the disease,” Smeyne added.

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Source: Parkinson's News Today

Parkinson’s May Share a Genetic Link with Crohn’s Disease, Study Finds

genetic link between Parkinson's, Crohn's

Mutations in the LRRK2 gene, a major genetic factor contributing to Parkinson’s disease, may likely affect the risk for Crohn’s disease, an inflammatory bowel disease, researchers at Mount Sinai in New York discovered.

The results suggest a potential genetic link between Crohn’s disease and Parkinson’s and common disease mechanisms. The findings should help researchers identify which patients are at risk for Crohn’s and aid in the development of new therapies that target these LRRK2 mutations.

“The presence of shared LRRK2 mutations in patients with Crohn’s disease and Parkinson’s disease provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases,” Inga Peter, the study’s lead author, said in a press release.

The study, “Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease,” was published in the journal Science Translational Medicine.

“Crohn’s disease is a complex disorder with multiple genes and environmental factors involved, which disproportionally affects individuals of Ashkenazi Jewish ancestry,” said Peter, a professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai in New York.

In an attempt to identify new therapeutic targets for this disease, researchers performed a genome-wide association analysis using data from 2,066 patients with Crohn’s and 3,633 healthy individuals, all from Ashkenazi Jewish descent.

The analysis revealed that members of this population carry two mutations in the LRRK2 gene with opposite effects – one has a protective effect while the other increases the risk for Crohn’s.

Because the LRRK2 gene has long been associated with Parkinson’s disease, researchers went on to assess a possible link between the two diseases. They used a much larger study group of 24,570 people with Crohn’s, Parkinson’s, or with no disease. Each individual group had both Jewish and non-Jewish individuals.

Once again, researchers found that patients with Crohn’s disease had a higher prevalence of the the risk mutation, while those without the disease more commonly had the protective mutation. Interestingly, these mutations had similar effects for Parkinson’s patients, and the effects were seen in both Jewish and non-Jewish patients.

“We now demonstrate that these specific nonsynonymous variants in LRRK2 genetically link [Crohn’s disease] to [Parkinson’s disease],” the team wrote.

Overall, “these results point toward potential shared genetic and epidemiological links between these two diseases and can help identify a sub-group of patients with [Crohn’s disease] who are at a higher risk for developing [Parkinson’s disease],” researchers concluded.

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Source: Parkinson's News Today