First Parkinson’s Patient Dosed in Early Trial of DNL151, Potential LRRK2 Inhibitor

DNL151 early trial

A Phase 1b clinical trial exploring the oral LRRK2 inhibitor DNL151 has started dosing Parkinson’s patients, the therapy’s developer Denali Therapeutics announced.

The 28-day, multicenter, and double-blind study (NCT04056689) is testing two doses of DNL151 against placebo in people with mild to moderate Parkinson’s disease, and with or without LRRK2 mutations, the most common genetic cause of the disease.

Twenty-four patients, ages 30 to 75, are expected to take part in the trial, and enrollment is ongoing at the Centre for Human Drug Research, in Leiden, the Netherlands. More information and contacts can be found here.

The company also announced the launch of its Engage Parkinsons website, where patients, caregivers, healthcare professionals, and advocates can find information about the disease and its link with genetics, overall advancements in Parkinson’s research, and Denali’s clinical trials. Registrants will also be informed about future studies sponsored by Denali.

“We are encouraged by the progress with our LRRK2 clinical program,” Ryan Watts, PhD, Denali’s CEO, said in a press release. “The launch of our Engage Parkinson’s website is intended to strengthen our engagement and interactions with the Parkinson’s disease patient community.”

“This is an important part of our efforts to connect with patients who may be eligible for our current and future clinical trials.”

DNL151 is a small molecule inhibitor of LRRK2, a protein that regulates the activity of cellular structures called lysosomes — tiny vesicle were a cell’s waste is broken down and recycled. High levels of LRRK2 impair lysosomal function, and may result in the formation of toxic protein clumps called Lewy bodies in brain cells. Lewy bodies are associated with neurodegeneration.

By selectively suppressing LRRK2, DNL151 aims to restore lysosomal function, which, according to Denali, may slow Parkinson’s progression in all patients.

The Phase 1b trial will primarily assess the safety, tolerability, pharmacokinetics — a compound’s absorption, distribution, metabolism, and excretion — and overall impact on the body of a high and low dose of DNL151. Biomarkers of target binding and exploratory clinical endpoints (goals) will also be evaluated.

Participants will be randomly assigned to either dose of DNL151, or a placebo. Study completion is expected by February 2020.

“Based on data generated from our prior study in healthy volunteer subjects, we are excited to evaluate DNL151 in Parkinson’s disease patients,” said Carole Ho, MD, Denali’s chief medical officer. “We believe that this study will provide additional important safety and biomarker data in patients to inform the choice between either DNL151 or DNL201 for potential registrational trials.”

These future trials are expected to form the basis of requests for regulatory approval of either therapy.

DNL201 is the company’s lead candidate for Parkinson’s disease, and is also an oral LRRK2 inhibitor able to reach the brain. A Phase 1 trial (NCT03710707) has a similar design to DNL151’s Phase 1 study, but is taking place at sites across the U.S. It is expected to conclude shortly.

Preclinical work supports the potential therapy’s ability to substantially inhibit LRKK2 activity even when administrated at lower dose.

Reported results of a prior Phase 1 study showed that DNL201 was safe and well-tolerated in healthy volunteers, and it demonstrated an ability to effectively suppress LRRK2 effects, as measured by blood biomarkers.

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Fox Foundation Awards $5M to Support Genetic Studies of Parkinson’s in Africa, Asia and India

Fox Foundation grant

With the overarching goal of helping scientists develop and test targeted therapies in Parkinson’s (PD), The Michael J. Fox Foundation (MJFF) is awarding $5 million in grants to three teams conducting genetic studies in African, East Asian and Indian populations.

The funding seeks to broaden these studies in order to better understand the role of genetics in PD onset and progression, and to expand treatment options for patients globally. Historically, the majority of research has focused on people of European descent. The grants will enable genetic testing of samples from more than 30,000 people.

“While the field has made significant strides in genetic research, we know we have more to learn about the changes in DNA that lead to Parkinson’s disease and impact its progression,” Brian Fiske, PhD, MJFF senior vice president of research programs, said a news release. “This is an all-star initiative with world-class geneticists, clinic networks and study volunteers coming together to paint a global picture of Parkinson’s and work toward cures for everyone.”

Since researchers discovered the first genetic mutation linked to PD in 1997, more than 80 others have been identified. Scientists are studying the cellular impact of these mutations, associated with about 15 percent of PD cases, in order to better understand Parkinson’s and possible ways of treating it.

Potential therapies aimed at proteins including LRRK2, one of the most commonly known genetic causes of Parkinson’s, are in clinical trials. Work like this is what the global Parkinson’s genetics program hopes to build upon. The non-profit foundation has long backed genetic studies, and diversity and inclusivity in clinical investigations.

Grants under this global program — with support from the Edmond J. Safra Foundation, a long-time partner of the Fox Foundation — will go to the following projects:

“Parkinson’s is a global issue, and we are grateful to The Michael J. Fox Foundation for fostering representation in research,” said Njideka Okubadejo, a professor of research at the University of Lagos in Nigeria. “We hope this partnership results in greater understanding of disease causes and contributors, and leads to new treatments for people living in Africa and beyond.”

Parkinson’s is the second most common age-related neurodegenerative disorder (after Alzheimer’s), and estimated to affect 7 to 10 million people worldwide.

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Lysosome-targeting Therapies Can Potentially Reverse LRRK2 Effects in Parkinson’s, Study Suggests

LRRK2 mutations

Mutations in the LRRK2 gene, which have been linked to familial Parkinson’s disease, impair the activity of the waste clearance system inside nervous brain cells, contributing to their progressive degeneration, a study finds.

Using a compound called clioquinol, researchers could restore the activity of lysosomes — the core centers of waste degradation — that was blocked by mutated LRRK2. This finding highlights the potential for lysosome-targeting therapies as a strategy for treating people with Parkinson’s and other neurodegenerative disorders.

The study, “LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function,” was published in the journal Human Molecular Genetics.

Parkinson’s is a chronic and progressive neurodegenerative disease caused by the loss of dopamine-producing neurons in the substantia nigra, a brain region involved in the control of voluntary movements. It remains unclear why this particular group of brain cells is more sensitive, but researchers believe that the cells’ death is due to the accumulation of toxic protein aggregates.

Recent findings suggest that lysosomes, special compartments within cells that digest and recycle different types of molecules, may play a role in this mechanism of protein buildup. When the lysosomes don’t function properly, waste accumulates inside cells instead of being degraded and cleared out.

Increasing evidence also suggests that both genetic and sporadic cases of Parkinson’s are linked to lysosomes malfunction.

One of the most common genetic causes associated with familial forms of Parkinson’s are mutations in the leucine-rich repeat kinase 2 gene, known as the LRRK2, which provides instructions for making a brain protein called dardarin. Although mutated LRRK2 is believed to contribute to malfunctioning lysosomes, its underlying mechanism remains unclear.

Researchers from the University of Oxford tackled this question, using a genetically modified rat model carrying a mutated version of the LRRK2 gene, called R1441C, which has been found in human patients.

They analyzed the rats’ neurons — including the dopamine-producing neurons whose loss underlies Parkinson’s — and found that the R1441C mutation prevented the binding of LRRK2 to a lysosomal protein called vATPase a1. This protein has the particular role of regulating the acidity inside lysosomes that is necessary to degrade cell waste.

To further confirm the association between mutated LRRK2 and lysosome impairment, the team treated nerve cells with clioquinol, a compound previously reported to modulate lysosomes acidity by regulating the levels of vATPase. Treatment with clioquinol reversed the effect of the LRRK2-R1441C mutation in lysosomes, and restored the activity of the cells’ waste disposal system.

“Our work identifies for the first time the very important role of LRRK2 in regulating the acidity and the normal function of the protein recycling centre, the lysosome, and identifies a new way to target this therapeutically in Parkinson’s,” Richard Wade-Martins, PhD, professor of Oxford’s department of physiology, anatomy and genetics (DPAG), and the study’s senior author, said in a press release.

“The demonstration that small molecules which directly target lysosome dysfunction, such as clioquinol, have potential therapeutic benefit for Parkinson’s disease, fits closely with the emerging consensus from genetics on this critical area of cell biology,” the researchers said.

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Early Genetic Mutations May Contribute to Mitochondria Dysfunction and Parkinson’s Development, Study Suggests

mitochondria NESCs PD

Genetic mutations and consequent impaired activity of mitochondria — known as the powerhouses of the cell — may be a first step contributing to the development of Parkinson’s disease later in life, a new study suggests.

The study, “Neural Stem Cells of Parkinson’s Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality,” was published in Stem Cell Reports.

Parkinson’s disease is characterized by the degeneration and death of a specific group of nerve cells — called dopaminergic neurons —  in the midbrain, which are responsible for producing a neurotransmitter called dopamine. This neurotransmitter acts as a chemical messenger used by nerve cells to communicate.

It remains unclear what exactly triggers these damaging effects, but several studies have provided evidence that both genetic and environmental factors play a critical role.

Mitochondria are small organelles inside cells that provide energy and are known as the cell’s “powerhouses.” Parkinson’s patients are known to have impaired mitochondria activity, which is believed to contribute to the underlying mechanisms of the disease. Still, mitochondria’s role in Parkinson’s disease remains elusive.

An international team of researchers has now found that stem cells carrying a mutated LRRK2 gene —  previously linked to familial and sporadic Parkinson’s cases — recapitulate key mitochondrial defects described only in mature dopaminergic neurons.

The team analyzed 13 cultures of human-derived neuroepithelial stem cells (NESCs) — early progenitors of brain cells — that were obtained from three Parkinson’s patients carrying the mutated LRRK2 gene and four age- and gender-matched healthy donors.

They found that patient-derived NESCs had significantly altered patterns of mitochondrial gene expression compared with NESCs from healthy donors. Also, LRRK2 mutated stem cells had more mitochondria but these had aberrant structures and showed reduced capacity to produce energy. Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.

Overall, these findings indicate that mutated LRRK2 “interferes with mitochondrial dynamics, suggesting reduced mitochondrial quality,” the researchers wrote.

Further analysis confirmed that Parkinson’s patient-derived NESCs had increased production of toxic oxygen reactive species (ROS) — involved in oxidative stress — and had reduced survival compared with stem cells from healthy donors, which was consistent with impaired mitochondria activity.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or ROS, are harmful to the cells and are associated with a number of diseases, including Parkinson’s disease.

In addition, patient-derived NESCs showed impaired ability to clear these damaged mitochondria, meaning that they were unable to restore the normal mitochondria balance and prevent their toxic effects.

“The detection of these (mitochondria features) in a developmentally early neural stem cell model” supports the hypothesis that “preceding mitochondrial developmental defects contribute to the manifestation of the (Parkinson’s disease) pathology later in life,” the researchers concluded.

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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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PIG3 Protein’s Role in Development of Familial Parkinson’s Detailed in Studies

PIG3 studies

Results from preclinical studies show the PIG3 protein as a key player in LRRK2-mediated familial Parkinson’s disease.

The findings were discussed in two presentations at the Society for Neuroscience (SfN) 2018 annual meeting in San Diego, California.

Mutations in the LRRK2 gene — the leading genetic cause of Parkinson’s — account for about 1 to 2 percent of all disease cases.

LRRK2 codes for the enzyme leucine-rich repeat kinase 2 (LRKK2), a protein that modifies other proteins’ activities, including signaling, replication, and gene expression.

All LRRK2 disease-causing mutations lead to higher LRKK2 enzyme activity; but the mechanism linking LRRK2 variants and Parkinson’s-related neurodegeneration is unclear.

Researchers used an approach they call “back to biology,” which is based on a platform developed by the biopharmaceutical company Berg, called Interrogative Biology. This platform — fueled by artificial intelligence — allows the analysis of several proteins from the same tissue sample, helping scientists to identify biomarkers that may speed the discovery and development of treatments aimed at promising therapeutic targets and pathways.

In the study “p53 inducible gene 3 (PIG3) directly modulates apoptotic responses in human neuronal models of Parkinson’s disease in vitro,” researchers identified a protein called PIG3 as an important mediator of the damage mutated LRRK2 does to nerve cells.

Researchers compared protein patterns in fibroblasts — specialized cells responsible for ensuring the normal structure of tissues — collected from Parkinson’s patients harboring the LRRK2G2019S mutation, idiopathic (no genetic or other known cause) Parkinson’s patients, and matched healthy volunteers.

Overall, patients with the LRRK2G2019S mutation had higher levels of the PIG3 protein. These were found to correlated with the activation of two enzymes, MKK3 and p38 MAPK, and with a buildup of the p53 protein — a protein that regulates the cell cycle and functions as a tumor suppressor (known as the “guardian of the genome”).

Further experiments with human dopamine-producing nerve cells showed linked higher PIG3 levels to cell death.

While experimental conditions that forced PIG3 production induced cell death, genetic or chemical blocking of PIG3 or LRRK2 activity were able to prevent neurodegeneration.

Researchers also found that PIG3 interacts with an enzyme called catalase, modulating the levels of oxidative stress — which damages cells as a consequence of high levels of oxidant molecules — and, consequently, of cell death.

“Our Back to Biology approach has further identified novel profiles driving disease activity – such as LRRK2 mutation and PIG3 expression – that we believe hold great potential for novel treatments for patients suffering from progressive, debilitating neurodegenerative disorders,” Niven R. Narain, PhD, a Berg co-founder and its CEO, said in a press release.

Researchers reprogrammed fibroblasts from both healthy individuals and LRRK2G2019S Parkinson’s patients to generate inducible-pluripotent stem cells (iPSC). These cells were programmed back into a stem cell-like state, allowing for the development of an unlimited source of any type of human cell.

iPSCs cells, from both patients and healthy controls, were then transformed (differentiated) into neurons, and the team was able to replicate their findings in these nerve cells, additional evidence for the role of PIG3 in Parkinson’s progression.

Next, researchers used the CRISPR/Cas9 system — a gene editing approach — to genetically delete the PIG3 coding gene in these iPSCs. Patients-derived iPSCs lacking the gene showed better cell survival in response to certain death-inducing stimuli.

“Our preliminary findings support the notion that PIG3 might serve as valuable and novel therapeutic target in Parkinson’s-specific pathologies,” researchers wrote.

In the study, “Altered cellular and metabolomic phenotypes observed in LRRK2G2019S patient-specific iPSC-derived neurons are partially rescued in PIG3-deficient cells,” researchers evaluated the  deteriorating function of LRRK2G2019S in patient iPSC-derived neurons.

By analyzing electrophysiological — the electric activity associated with nerve cell functions — and metabolomic  — chemical processes involved in several cellular processes — profiles in dopaminergic neurons derived from iPSCs, researchers found that Parkinson’s-derived neurons (nerve cells) had different patterns of activity patterns and altered metabolomic profiles.

These included different neuronal firing rates (electrical pulses necessary for nerve cell communication), burst frequencies (oscillations in neuronal activation patterns), and network synchrony (involved in regulating information transmission through the nervous system).

“Taken together, our findings reveal that PIG3 contributes to apoptosis in neuronal models of Parkinson’s disease, and may advance our understanding of the mechanisms behind LRRK2 G2019S-mediated hypersensitivity to environmental neurotoxins, and neuronal dysfunction,” the researchers concluded.

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Data Lacking on Link Between Genetic Mutations and Parkinson’s Symptoms, Review Finds

genetic mutations, symptoms

There is a substantial lack of data describing the link between the genetic mutations identified as inheritable causes of Parkinson’s — those that affect the SNCA, LRRK2, and VPS35 genes — and patient symptoms, a review study has found.

Despite this missing information, the researchers conducting the review were still able to make some determinations, including findings indicating that SNCA mutation carriers are younger in age at disease onset and have additional psychiatric symptoms, while VPS35 mutation carriers have a good response to levodopa therapy.

The study, “Genotype‐phenotype relations for the Parkinson’s disease genes SNCA, LRRK2, VPS35: MDSGene systematic review,” was published in Movement Disorders.

Parkinson’s disease, the second most prevalent neurodegenerative disease in the elderly after Alzheimer’s disease, is a complex, multifactorial disorder characterized by the gradual loss of muscle control, sometimes accompanied by cognitive deficits.

Previous studies have estimated that genetic factors may account for up to 34 percent of all Parkinson’s cases. More specifically, genetic mutations in the SNCA, LRRK2, and VPS35 autosomal genes (genes located on any chromosome other than sex chromosomes) are considered a cause of disease in up to 30 percent of all patients with Parkinson’s, depending on family history, age at onset, and population background.

“The International Parkinson and Movement Disorder Society Genetic mutation database (MDSGene) aims to systematically collect clinical and genetic information for movement disorder patients who have pathogenic mutations. In this study, we present a systematic MDSGene review and devote it to autosomal-dominant PD [Parkinson’s disease] across the three disorders, PARK-SNCA, PARK-LRRK2, and PARK-VPS35,” the researchers wrote.

The comprehensive, systematic review gathered information from 199 studies (54 on SNCA, 133 on LRRK2, and 12 on VPS35) involving a total of 937 patients (146 SNCA, 724 LRRK2, and 67 VPS35 mutation carriers) with inherited Parkinson’s disease attributed to 44 different mutations in these three genes.

“A major challenge for this systematic review was the degree of missingness of phenotypic [disease symptoms] data. Missing data not only affected non-motor signs and symptoms (NMS) of all patients, but specific information was even often unavailable for basic demographic information such as age at onset or sex or cardinal motor signs,” the authors said.

Despite the lack of data, the review managed to validate findings from previous studies showing that patients carrying mutations in the SNCA gene were more likely to develop Parkinson’s disease at an earlier age than those carrying mutations in LRRK2 and VPS35.

Pooled data also revealed that SNCA mutation carriers more frequently experienced psychiatric symptoms, while LRRK2 mutation carriers rarely had atypical symptoms of Parkinson’s disease. The researchers also found that VPS35 mutation carriers responded rather well to levodopa therapy.

“The most significant finding is the proportion of missing phenotypic data. … We propose to utilize MDSGene as the basis for the systematic collection of curated clinical and genetic information on inherited movement disorders as a solution to increase reporting of phenotypes for better genetic counseling and future gene-specific therapies,” the researchers wrote.

“To this end, the MDS Task Force on Genetic Nomenclature in Movement Disorders is drafting checklists that we propose should become the standard for clinical data reporting of individuals with movement disorders. Standard reporting of core features could improve the situation considerably,” they concluded.

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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.

The post Therapies Targeting LRRK2 Gene Could Benefit Broad Population of Parkinson’s Patients, Study Finds appeared first on Parkinson’s News Today.

Source: Parkinson's News Today

Synaptic Vesicle Defect Leads to Neurodegeneration in Parkinson’s, Study Suggests

synaptic vesicle

Impaired intake of neurotransmitters leads to accumulation of toxic dopamine and neurodegeneration in patients with Parkinson’s disease, according to a new Northwestern Medicine study.

The study, “LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease,” appeared in the journal Proceedings of the National Academy of Sciences.

Parkinson’s is characterized by a substantial loss of neurons that produce the neurotransmitter dopamine in a brain area called substantia nigra. Prior research conducted by a team led by Dimitri Krainc, MD, PhD, chair and Aaron Montgomery Ward Professor of Neurology at Northwestern, showed that the accumulation of oxidized dopamine in the brain regulates the death of these neurons, which leads to Parkinson’s motor symptoms.

In neurons, neurotransmitters are stored in tiny vesicles near the synapse. Scientists have recently found genes associated with Parkinson’s involved in the transport of vesicles from these synaptic terminals toward the cell’s interior, a process called endocytosis. Through endocytosis, neurons replenish the levels of neurotransmitters to enable continued communication.

This discovery supported the importance of impaired neuronal communication, or synaptic dysfunction, in disease development, but the precise mechanisms leading to neuronal death remained unknown.

“In this paper, we further explain how such oxidized dopamine is formed in synaptic terminals of neurons from patients with Parkinson’s,” Krainc, the study’s senior author, said in a press release.

Results showed that a mutated form of the Parkinson’s-associated enzyme LRRK2 dysregulates auxilin, a protein normally responsible for synaptic vesicle endocytosis. This led to faulty endocytosis and decreased density of vesicles in patient-derived dopaminergic neurons.

Importantly, the scientists also observed that impaired endocytosis led to accumulation of oxidized dopamine in neurons. In turn, this buildup of toxic dopamine caused Parkinson’s-related effects, including an increase in alpha-synuclein, the main component of protein clumps called Lewy bodies.

“Together, this work suggests that mutant LRRK2 disrupts synaptic vesicle endocytosis, leading to altered dopamine metabolism and dopamine-mediated toxic effects in patient-derived dopaminergic neurons,” the investigators wrote in the study.

“These findings suggest that early therapeutic intervention in dysfunctional presynaptic terminals may prevent downstream toxic effects of oxidized dopamine and neurodegeneration in [Parkinson’s],” Krainc said in the release.

Additionally, investigating genetic forms of Parkinson’s contributes to increased understanding of key cellular mechanisms in the development of the disease, the researchers noted.

“This study is another example of how the emergence of genetic causes of Parkinson’s has helped us understand how disease develops and where to focus to identify key pathways and targets for drug development,” Krainc said.

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Source: Parkinson's News Today