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

ROPAD study, Parkinson's genetics

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

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

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

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

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

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

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

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

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

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

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

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Mutations on NUS1 Gene Can Significantly Raise Person’s Risk of Parkinson’s, Study Reports

NUS1 mutations

Mutations affecting the NUS1 gene are linked to a significantly increased risk — 11 times higher — of developing Parkinson’s disease, study shows.

The study, “Coding mutations in NUS1 contribute to Parkinson’s disease,” was published in Proceedings of the National Academy of Sciences.

Although exact triggers of Parkinson’s disease remain unclear, aging, and environmental and genetic factors are believed to be major culprits.

SNCA was the first gene to be linked to the development of Parkinson’s. Since its discovery in 1997, scientists have attempted to find other genes that may also play a role.

Chinese researchers conducted a detailed genetic analysis of samples collected from 39 patients with early-onset Parkinson’s disease, their parents, and 20 unaffected siblings, aiming to detect de novo mutations associated with the disease.

A de novo mutation is a genetic alteration evident for the first time in one family member as a result of a mutation in the egg or sperm of a parent, or a mutation that arises in the fertilized egg itself during early development. A child with a de novo (new) mutation will develop the associated disease, while his parents or siblings will not.

Researchers identified 12 genes carrying de novo mutations — MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2. These genes are known to be expressed in two brain regions affected in Parkinson’s disease, called the stratum and substantia nigra, and could be functionally relevant to early-onset Parkinson’s.

Biologic network analysis showed that all the identified genes may share similar biological functions, and act together to increase the risk of developing Parkinson’s.

Patients did not have any other genetic variants previously associated with the disease.

Next, researchers explored the presence of rare mutations in these 12 genes in samples collected from 1,852 patients with sporadic (non-familial) Parkinson’s disease and 1,565 healthy volunteers. In this secondary screening, no significant alterations were found with exception of the NUS1 gene.

To confirm this finding, the team performed a detailed analysis of the NUS1 gene in a larger number of samples (3,237 patients and 2,858 controls). Similar to the previous analysis, Parkinson’s patients carried NUS1 mutations that were not present in the (healthy) control samples.

The presence of NUS1 variants, and consequent lower levels of the gene, were associated with a 11.3 times higher risk of having Parkinson’s disease.

Researchers also examined the role of the NUS1 gene in vivo, by deleting the equivalent gene — which shares 44% similarly with the human NUS1 — in a fly model (Drosophila). They observed that this deletion induced the loss of dopamine-producing nerve cells and, consequently, lower brain dopamine levels — two main hallmarks of Parkinson’s disease.

“These data … suggest that NUS1 plays important roles in dopamine neurons and that the loss of NUS1 could lead to neuronal dysfunction that is related to Parkinson’s disease,” the researchers wrote.

“[D]e novo mutations could contribute to early onset PD [Parkinson’s disease] pathogenesis and identify NUS1 as a candidate gene for PD,” they 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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New Scoring System Identifies Relevant Genes Involved in Parkinson’s Disease

genes scoring system

Johns Hopkins researchers have developed a new scoring system intended to help identify genes that might be important factors in the development of sporadic Parkinson’s disease.

This new approach is expected to accelerate the identification of relevant genetic biomarkers that require further study while helping researchers avoid “dead-end paths.”

The study, “Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease,” appeared in The American Journal of Human Genetics.

New technologies that analyze a cell’s genetic content have greatly increased knowledge of gene variations that can cause disease. These genome-wide association studies (GWAS) were initially designed to provide a general overview of disease-associated genetics. As a result, they have provided large amounts of data that can be difficult to decipher because they only identify regions of the genetic code where there could be hundreds of genes potentially affected by a mutation.

As such, these studies can identify genetic mutations, but they do not always pinpoint a single gene. Scientists believe there is, at best, a 50 percent chance that the gene closest to a mutation will be active in the cell types affected by a disease.

“We are in a scenario where we can collect massive amounts of genetic data using GWAS, but are realizing that does not provide the biological context we need in order to understand the results,” Andrew McCallion, PhD, associate professor at the Johns Hopkins University School of Medicine and senior author of the study, said in a press release.

To help read this data, McCallion and his team developed a method to filter the information. They focused on Parkinson’s disease for which GWAS have identified 49 genome regions with a mutation related to the disease.

“Strategies [that can systematically identify biologically pertinent gene candidates] are necessary for the community to take full advantage of the immense body of GWAS data now in the public domain,” the researchers wrote.

The team analyzed the genetic content of different dopaminergic brain cell populations — those affected in Parkinson’s — collected from mice at early stages of development (embryonic and early postnatal). This approach allowed the team to build a genetic profile of 13 dopaminergic cell types and identify gene regulatory networks in these cells.

Based on the collected data, researchers established a framework to systematically prioritize Parkinson’s candidate genes, and validated their system in the 49 genome regions GWAS had already found.

Using this novel strategy, they were able to pare down the list of potential genes from an initial 1,751 to 112.

Of the genes involved in Parkinson’s disease in these specific regions, their strategy captured all but one. “However, the one we didn’t capture is not expressed in dopaminergic neurons,” McCallion said. “This gives us confidence that the other genes pointed out will be important to the disease.”

The team now wants to investigate if age, environment, and disease state in dopaminergic brain cells can help to further fine-tune their scoring system.

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Source: Parkinson's News Today