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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.

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

LRRK2

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

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

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

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

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

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

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

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

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

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

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

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

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

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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

Charles River Laboratories, Michael J. Fox Foundation Extend Research Partnership

Charles River Laboratories

Charles River Laboratories International and The Michael J. Fox Foundation for Parkinson’s Research (MJFF) extended their collaboration to accelerate the discovery of Parkinson’s disease therapies.

The extension covers grants from MJFF to characterize two animal models of Parkinson’s — one where mice do not express alpha-synuclein (knockout), and another where mice express the Parkinson’s-associated alpha-synuclein mutant A53T (knockin). Alpha-synuclein is the major component of Lewy bodies, the characteristic protein clumps of Parkinson’s disease.

Charles River and MJFF also renewed their partnership to continue to develop and test new small molecules that inhibit the LRRK2 kinase, whose mutations are associated with the development of sporadic and familial cases of Parkinson’s.

Two LRRK2 inhibitors, currently being evaluated to treat Parkinson’s in two Phase 1 clinical trials, already have shown promising initial results.

Researchers want to establish optimal dosing strategies for efficient LRRK2 inhibitors, while avoiding lung changes that have been reported in previous preclinical studies in animal models.

Charles River will work on these projects for the next two years,  providing novel preclinical tools for drug development in Parkinson’s disease.

“We are enthusiastic about the start of our new project,” Robert Hodgson, PhD, director In Vivo CNS, Integrated Drug Discovery at Charles River, said in a press release. “It is extremely rewarding for our teams to know that they are making visible progress toward bringing a novel [Parkinson’s] therapy to the clinic.”

Nicole Polinski, PhD, associate director of Research Programs at MJFF, added: “The Michael J. Fox Foundation is committed to advancing tools and pre-clinical models that speed Parkinson’s research toward urgently needed breakthroughs for patients.”

Polinski also underscored Charles River’s portfolio of early discovery services. “We look forward to seeing the outcomes of these projects, which may have a significant impact on development of new treatments for the millions living with this disease,” she said.

MJFF is the largest private funder of Parkinson’s research worldwide and collaborates with pharmaceutical companies, academic scientists and government research funders. The foundation also is involved in improving patient recruitment for clinical trials with its online tool, Fox Trial Finder, and in promoting disease awareness.

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Source: Parkinson's News Today