Oncodesign and Servier Hit First Milestone in Developing LRRK2 Inhibitors for Parkinson’s

Parkinson's, partnership

Oncodesign and Servier have reached the first key milestone months ahead of schedule in their partnership to develop LRRK2 inhibitors for Parkinson’s disease, the companies announced in a press release.

“The collaboration works perfectly and both teams are up to the challenges,” said Philippe Genne, PhD, Oncodesign’s founder and CEO. “The results were obtained sooner than expected which allowed us to reach our first milestone several months in advance.”

Mutations in the gene leucine rich repeat kinase 2 (LRRK2) are one of the most common genetic causes of Parkinson’s disease. Furthermore, even when there isn’t a disease-causing mutation, the LRRK2 protein tends to be overly active in the brains of people with Parkinson’s. This abnormally high activation causes problems in the molecular machinery that brain cells use to recycle proteins, which is thought to be involved in Parkinson’s by promoting the abnormal aggregation of proteins such as alpha-synuclein.

Preclinical research has suggested that blocking LRRK2 activity could be therapeutic in Parkinson’s disease, and such investigational therapies are in early clinical trials.

Servier and Oncodesign entered into a partnership to design new LRRK2 inhibitors in March 2019. The partnership involves the use of Nanocyclix, a proprietary technology owned by Oncodesign, which facilitates the discovery of small molecules that can block the activity of protein kinases such as LRRKs.

“Reaching this first important milestone in such a challenging program speaks to the potential of the Nanocyclix series of molecules that we pursue,” said Jan Hoflack, PhD, scientific director at Oncodesign. “[T]heir potency and selectivity within very small molecular weight compounds are ideal assets for this difficult CNS [central nervous system] program. It also speaks to the highly collaborative approach between Servier and Oncodesign.”

Hitting the first milestone triggered a payment of 1 million euros (about $1.08 million USD) to Oncodesign.

“We are very pleased with the rapid progress we have made together with Oncodesign in this collaborative program, with a very efficient and dynamic joint team, and look forward to continuing success over the coming years to reach our common goal of bringing a new treatment for patients,” said Christophe Thurieau, executive director of the Servier Research Institute.

The post Oncodesign and Servier Hit First Milestone in Developing LRRK2 Inhibitors for Parkinson’s appeared first on Parkinson’s News Today.

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.

The post Mouse-brain Computer Model Tracks Spread of Alpha-synuclein in Parkinson’s appeared first on Parkinson’s News Today.

Researchers Find New Enzyme That Might Aid in ‘Putting the Brakes’ on Parkinson’s Disease

new enzyme

Researchers have discovered a new enzyme that might aid in “putting the brakes” on Parkinson’s by inhibiting the LRRK2 pathway, known to play a critical role in this neurodegenerative disease.

The findings are still at an early stage, but the team is already trying to find compounds that can switch on this enzyme in the hopes of finding a new therapy that can slow down Parkinson’s disease.

The study, “PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins,” was published in the journal eLife.

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.

LRRK2 works as an enzyme with kinase activity. This type of proteins, called kinases, assist in the transfer of a phosphate group — a molecule made of oxygen and phosphorus — to certain proteins. Such modification is called phosphorylation and is an essential step in turning on and off many proteins inside the cell.

Mutations that increase LRRK2 kinase activity lead to toxic effects on the nervous system, believed to play a central role in the development of Parkinson’s. Thus, looking for therapies that inhibit LRRK2 is a potential path to slow the degenerative process and could have therapeutic potential for Parkinson’s.

From a prior screening, scientist Dario Alessi’s team at the University of Dundee in Scotland already knew that human cells produced some sort of enzyme that could reverse LRRK2 activity.

Together with colleagues at Stanford University, Alessi and his team tried to discover what this enzyme was. Using human cell lines cultured in the lab, they found one — called protein phosphatase 1H (PPM1H). This enzyme is naturally produced in the body and is able to counteract LRRK2 signals. Specifically, it unlocks a type of proteins called Rab, which are inappropriately blocked by LRRK2.

“Parkinson’s is like a runaway train — at present we have no way of putting the brakes on to slow it down, let alone stop it. This new enzyme we have found acts as the brakes in the pathway that causes Parkinson’s in humans,” Alessi said in a press release.

“We have known for many years that the LRRK2 pathway is a major driver behind Parkinson’s but the concept of developing an activator of the PPM1H system to treat the disease is completely new. This finding opens the door for a new chemical approach to the search for Parkinson’s treatments,” added Alessi, PhD, university professor and director of the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU).

So far, approaches to block LRRK2 have focused on developing compounds that inhibit the LRRK2 kinase.

“But even once this is done we don’t know how well such a drug will be tolerated in the body so we are also looking for other ways to switch off this pathway. The purpose of this research was to find an enzyme that naturally stops LRRK2 by mediating these toxic pathways,” Alessi said.

There currently are no treatments able to slow the progression of Parkinson’s disease. “So we need to be throwing the kitchen sink at this problem,” Alessi said.

As the PPM1H enzyme appears to be present in all people, including those with Parkinson’s, Alessi said a breakthrough could be far-reaching.

“If we can find a way of switching this on then it theoretically could benefit all,” he said. “It also raises another exciting question that we want to study — is PPM1H higher in the brain of certain people and, if so, is this protecting them against Parkinson’s?”

Alessi and his colleagues have already started to work with the university’s Drug Discovery Unit to search for a compound able to switch on PPM1H, which could represent a potential treatment for Parkinson’s.

“This will be challenging work but if we can identify appropriate drug-like molecules then the next stage would be to test them in cells and in animal models to see if they do indeed switch off this pathway. If that works it would be certain to stimulate further preclinical activity and could potentially lead to a new way to treat Parkinson’s,” Alessi said.

The research was supported by the Michael J. Fox Foundation and the UK Medical Research Council.

The post Researchers Find New Enzyme That Might Aid in ‘Putting the Brakes’ on Parkinson’s Disease appeared first on Parkinson’s News Today.

Genetic Parkinson’s More Common Than Thought, Global Survey Reveals

Genetic PD survey

Cases of inherited Parkinson’s disease may be more frequent than previously reported, results from an online global survey suggest.

The survey, which was conducted by members of The Michael J. Fox Foundation Global Genetic Parkinson’s Study Group (MJFF-GGPSG), also revealed the willingness of investigators to share clinical information on their patients that could be useful to conduct broader and more inclusive studies.

These findings suggest it is necessary to improve the way investigators communicate and assess clinical data. It also highlights the need of new integrative research approaches that can empower teams to enhance the understanding and recognition of genetic mutations contributing to the development of Parkinson’s disease. This could be an important step to improve early diagnosis and define preventive strategies.

The results, “Identifying genetic Parkinson’s disease patients worldwide: Exploiting novel ways of team science,” were presented as a scientific poster during the International Congress of Parkinson’s Disease and Movement Disorders in Nice, France.

“This initiative is of high relevance because it is becoming increasingly clear that even relatively common diseases like Parkinson’s disease are highly etiologically heterogeneous syndromes and that progress towards early diagnosis and causative treatments will depend on the identification of sufficient numbers of well-defined subgroups,” Thomas Gasser, MD, said in a press release. Gasser is director of the department of neurodegeneration at Hertie Institute for Clinical Brain Research, in Tuebingen, Germany.

“This will only be possible by collaborations at a very large, preferably worldwide scale,” he said.

The survey, which was conducted in 2018, was designed to evaluate the availability of demographic, clinical, genetic, and additional data of patients with genetic Parkinson’s disease. It included cases caused by SNCA, LRRK2, VPS35, PRKN, PINK1, PARK7, and GBA mutations.

MJFF-GGPSG researchers addressed the survey to 336 investigators who were selected based on articles that had been published about the subject and were represented at the Movement Disorder Society Genetic mutation database (MDSGene), and through the Genetic Epidemiology of Parkinson’s disease (GEoPD) consortium.

Of the 336 investigators invited to participate in the survey, 162 (48%) responded, 98% of whom indicated interest in further collaboration.

“The overwhelmingly positive response and willingness to collaborate impressively highlight the relevance and power of team science,” the researchers wrote.

Researchers reported information from a total of 8,453 Parkinson’s patients with genetic mutations; more than nine different ethnicities were followed at 103 international sites across 43 countries.

Overall, mutations in the SNCA, VPS35, PINK1, and PARK7 genes were present in 3% (263 patients), 0.4% (35 patients), 3% (260 patients) and 0.3% (29 patients) of this patient population.

The most commonly affected genes were LRRK2, GBA, and PRKN, with mutations present in 38% (3,182 patients), 37% (3,154 patients), and 18% (1,530 patients).

These frequencies are particularly significant given that they represent a threefold higher number of patients with mutations associated with Parkinson’s disease when compared to the cases reported in the literature.

More than 98% of investigators who responded to the survey noted they had demographic data on their patients, with 94% of them having age-at-onset information, and only 66% reported having information on patients’ non-motor signs.

Most investigators (85%) had DNA samples from the patients, while only 8% had cerebrospinal fluid (CSF) samples. (CSF is the liquid that surrounds the brain and spinal cord.)

“This survey is only a very first small step. If international team science is to become successful, many problems concerning standardization of patient ascertainment, data privacy and protection as well as data access and use need to be solved,” Gasser said.

“Nevertheless, the survey raises awareness of these issues and it clearly shows that the Parkinson’s disease research community is ready to begin to tackle these important issues,” he said.

The post Genetic Parkinson’s More Common Than Thought, Global Survey Reveals appeared first on Parkinson’s News Today.

Specific Parkinson’s Gene Mutation Linked to Higher Risk of Leukemia, Colon Cancer, Study Finds

gene mutation cancer risk

People with Parkinson’s disease who have a specific mutation in the LRRK2 gene may be 10 times more likely to develop leukemia, and twice as likely to have colon cancer, researchers report.

The researchers say this particular patient population should be closely monitored and screened for the early detection of cancer.

These findings, “Cancer Outcomes Among Parkinson’s Disease Patients with Leucine Rich Repeat Kinase 2 Mutations, Idiopathic Parkinson’s Disease Patients, and Nonaffected Controls,” were published in Movement Disorders.

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are one of the most commonly known genetic causes of Parkinson’s disease. They 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.

Different studies indicate Parkinson’s patients with a specific mutation in the LRRK2 gene, known as G2019S, have an increased risk of developing certain cancers compared with people with Parkinson’s disease of unknown cause.

“However, it is unclear whether the increased risk among LRRK2-PD [Parkinson’s disease] patients would be observed when compared with unaffected controls who are noncarriers of the G2019S mutation,” the researchers said.

Investigators from the Albert Einstein College of Medicine and Mount Sinai Beth Israel Medical Center sought to compare the prevalence of cancer among Parkinson’s patients with the LRRK2 mutation, people with Parkinson’s of unknown cause (also called idiopathic Parkinson’s), and healthy individuals (controls). To do so, they used a standardized questionnaire across seven international LRRK2 and Parkinson’s-related research centers.

The gathered data was then combined with previously published information to examine the associations between the LRRK2 G2019S mutation and several types of cancer.

Researchers studied the cancer outcomes of 257 LRRK2 G2019S Parkinson’s patients, 712 people with idiopathic Parkinson’s, and 218 genetically unrelated controls, ages 35 or older. On average, the Parkinson’s patients were 68.2 years old, while the control sample was 4 years younger, with a mean age of 64 years. Around 77% of study subjects were Ashkenazi Jews, who more commonly carry genetic mutations linked to Parkinson’s, such as LRRK2.

Results showed there were no significant differences in the cancer rates of all three study groups. In fact, the rates were similar: 32.3% for LRRK2 G2019S Parkinson’s patients, 27.5% for idiopathic Parkinson’s, and 27.5% for controls.

Nevertheless, individuals with the LRRK2 G2019S mutation had a 4.6-fold increased risk of developing leukemia, and a 1.6-fold higher risk of developing skin cancer. Researchers note that only 5 of the 257 people with LRRK2 G2019S Parkinson’s developed leukemia, compared with no cases in the idiopathic Parkinson’s group. Further analysis also suggested higher risks for colon and kidney cancers in LRRK2 G2019S Parkinson’s, but statistical significance was not attained.

Scientists then combined this data with that of a previous study, which led to an overall study pool totaling 401 people with LRRK2 G2019S Parkinson’s and 1,946 individuals with the idiopathic form of the neurodegenerative disorder.

The pooled analysis revealed that individuals with LRRK2 G2019S were 9.84 times more likely to develop leukemia, and 2.34 times more likely to develop colon cancer, in comparison with idiopathic Parkinson’s patients.

These findings indicate the LRRK2 G2019 mutation might be associated with the development of several types of cancer.

“We might consider that if someone is a carrier of the LRRK2 G2019S mutation they should be closely monitored for Parkinson’s and for certain cancers,” Ilir Agalliu, MD, PhD, associate professor in the department of epidemiology and population health at Albert Einstein College of Medicine, and first author of the study, said in a press release.

The post Specific Parkinson’s Gene Mutation Linked to Higher Risk of Leukemia, Colon Cancer, Study Finds appeared first on Parkinson’s News Today.

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.

The post First Parkinson’s Patient Dosed in Early Trial of DNL151, Potential LRRK2 Inhibitor appeared first on Parkinson’s News Today.

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.

The post Fox Foundation Awards $5M to Support Genetic Studies of Parkinson’s in Africa, Asia and India appeared first on Parkinson’s News Today.

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.

The post Lysosome-targeting Therapies Can Potentially Reverse LRRK2 Effects in Parkinson’s, Study Suggests appeared first on Parkinson’s News Today.

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.

The post Early Genetic Mutations May Contribute to Mitochondria Dysfunction and Parkinson’s Development, Study Suggests appeared first on Parkinson’s News Today.

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.”

The post Inflammatory Signals from Non-neuronal Cells Linked to Neurodegeneration in Fly Study appeared first on Parkinson’s News Today.