PRKN

Initial data from largest international Parkinson’s disease patient cohort shows approximately 90% of these genetically confirmed patients had variants in the LRRK2 or GBA1 genes, making these individuals potential candidates to be included in gene-targeted trialsThe Rostock International Parkinson's Disease (ROPAD) Study aims to characterize the genetics of Parkinson’s disease (PD) to establish a better understanding of disease progression, diagnosis, and treatment for patients CAMBRIDGE, Mass. and ROSTOCK, Germany and BERLIN, Aug. 01, 2024 (GLOBE NEWSWIRE) -- Centogene N.V. (Nasdaq: CNTG), the essential life science partner for data-driven answers in rare and neurodegenerative diseases, today announced data from the Company’s Rostock International Parkinson's Disease (ROPAD) Study revealing the genetic factors and prevalence of Parkinson’s disease (PD). The findings from this landmark study indicate that approximately 15% of PD-related cases are tied to genetic variants, with the majority being linked to LRRK2 and GBA1. The data was published in Brain in a paper titled, “Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson’s disease study.” “Over the past five years, CENTOGENE and our more than 100 study sites around the world have worked together to diagnose Parkinson’s patients and accelerate treatment options,” said Prof. Peter Bauer, Chief Medical and Genomic Officer at CENTOGENE. “Our collaborative work clearly shows how significant of a role genetics plays in Parkinson’s disease and underscores the need to integrate genetic testing in routine care of these patients. This will not only enable access to potentially available treatments, but will de-risk and accelerate the development of gene-specific therapies – driving the future of Parkinson’s disease patient care.” The research investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap from over 12,500 patients from 16 countries who have been enrolled in CENTOGENE’s ROPAD Study. In more than 1,800 participants, a PD-relevant genetic test (PDGT) provided a positive result. This included variants linked to the LRRK2 and GBA1 genes, as well as PRKN, SNCA, and PINK1, or a combination of genetic findings in multiple genes. In the emerging era of gene-targeted PD clinical trials, the Company’s findings that approximately 15% of patients harbor potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. By capturing such genetic data, this also allows for differential genetic counselling across the spectrum of different ages at onset and family histories. The Company recently launched a ROPAD Consortium to continue driving PD research and treatment through collaborative efforts. The ROPAD Consortium will build on the vast network of neurologists, existing partnerships with non-profit organizations, and the largest genetic testing program for PD patients worldwide to streamline access to critical data, drive impactful research, and improve the potential for advancing treatment options. To find out more, email: contact.pharma@centogene.com About ROPAD The Rostock International Parkinson's Disease (ROPAD) Study is a global epidemiological study focusing on the role of genetics in Parkinson’s disease (PD). The major goal of the study is to characterize the genetics of PD to establish a better understanding of the disease etiology, diagnosis, and severity. CENTOGENE utilizes CentoCard®, the Company’s proprietary, CE-marked Dried Blood Spot (DBS) collection kit in combination with state-of-the-art sequencing technologies to screen for mutations in LRRK2 and other PD-associated genes. To date, over 18,000 participants from around the world have been tested over a five-year period. About CENTOGENE CENTOGENE’s mission is to provide data-driven, life-changing answers to patients, physicians, and pharma companies for rare and neurodegenerative diseases. We integrate multiomic technologies with the CENTOGENE Biodatabank – providing dimensional analysis to guide the next generation of precision medicine. Our unique approach enables rapid and reliable diagnosis for patients, supports a more precise physician understanding of disease states, and accelerates and de-risks targeted pharma drug discovery, development, and commercialization. Since our founding in 2006, CENTOGENE has been offering rapid and reliable diagnosis – building a network of approximately 30,000 active physicians. Our ISO, CAP, and CLIA certified multiomic reference laboratories in Germany utilize Phenomic, Genomic, Transcriptomic, Epigenomic, Proteomic, and Metabolomic datasets. This data is captured in our CENTOGENE Biodatabank, with over 850,000 patients represented from over 120 highly diverse countries, over 70% of whom are of non-European descent. To date, the CENTOGENE Biodatabank has contributed to generating novel insights for more than 300 peer-reviewed publications. By translating our data and expertise into tangible insights, we have supported over 50 collaborations with pharma partners. Together, we accelerate and de-risk drug discovery, development, and commercialization in target and drug screening, clinical development, market access and expansion, as well as offering CENTOGENE Biodata Licenses and Insight Reports to enable a world healed of all rare and neurodegenerative diseases. To discover more about our products, pipeline, and patient-driven purpose, visit www.centogene.com and follow us on LinkedIn. Contacts:Melissa HallCENTOGENECorporate Communications Press@centogene.com Lennart StreibelCENTOGENEInvestor Relations IR@centogene.com

Researchers uncovered the mechanistic details behind how several proteins interact to help cells recognize and remove damaged mitochondria. Optineurin (OPTN) and its interactions are needed to provide a contact site for another protein, Tank-binding kinase 1 (TBK1), during this process. The OPTN-TBK1 relationship is necessary for these mitochondria to be recognized and eliminated from the cell. This mechanism may have relevance for developing drugs to treat Parkinson's disease. Autophagy is a process used by cells as a recycling system to transport and break down organelles and other cytosolic components, which become enveloped in a membrane called the autophagosome (Fig 1). When this involves the removal of damaged mitochondria, commonly called the "powerhouse" of the cell, it is known as mitophagy. In a recent article published in The EMBO Journal, a team led by researchers at Tokyo Medical and Dental University (TMDU) elucidated the molecular details of how an enzyme called Tank-binding kinase 1 (TBK1) participates in a disease-relevant mitophagy mechanism. Although autophagy has been characterized as a more general process meant to degrade and clear various cellular components, recent data have suggested that certain pathways are specifically involved in the autophagy of particular organelle types that are damaged or no longer needed. The researchers became interested in mitophagy mediated by molecules called PINK1 and Parkin, as they are proteins that have been pathologically linked to Parkinson's disease. "Mitophagy-related defects have been directly implicated in the neurodegeneration observed in Parkinson's disease patients," says Koji Yamano, lead author of the study. "Normally, PINK1 and Parkin work together to mark damaged mitochondria for removal by adding a chain of molecules called ubiquitin. This mark allows proteins called autophagy adaptors to associate with the mitochondria and bring in the autophagy machinery for autophagosome development." Although TBK1 is known to participate in PINK1/Parkin-mediated mitophagy, a detailed mechanism how it activates remained unclear. Using various molecular biology techniques, the team found that deleting the gene encoding TBK1 prevented association of an autophagy adaptor called optineurin (OPTN) during Parkin-mediated mitophagy (Fig 2). Additionally, deleting the OPTN gene prevented autophosphorylation of TBK1, which is necessary for it to function. Further work suggested that the interactions between OPTN and ubiquitin, as well as between OPTN and the developing autophagosome, were all needed for OPTN and TBK1 to come together at the contact site between damaged mitochondria and the pre-autophagosome membrane. Without this contact site, TBK1 autophosphorylation could not occur. The researchers also generated molecules called monobodies in their lab that could specifically bind OPTN and inhibit its physical interactions. The monobodies prevented OPTN accumulation at the mitophagy contact sites (Fig 3A). This subsequently blocked TBK1 activation (Fig 3B) and thereby mitochondrial degradation. These experiments further emphasized the importance of the OPTN-TBK1 relationship to support proper mitophagy. "Because PINK1 and Parkin are critical contributors to the molecular basis of Parkinson's disease, understanding the mechanistic details related to the mitophagy process mediated by these molecules is very important," explains Yamano. This study demonstrates a positive and reciprocal relationship between OPTN and TBK1 that is necessary for autophagosomes to begin forming on damaged mitochondria. The impactful finding may lead to the development of novel drugs to treat Parkinson's disease.

Researchers have shown that a protein called HKDC1 is a new target of another protein, TFEB, and plays key roles in maintaining the stability of both mitochondria and lysosomes. HKDC1 is essential for mitophagy to remove damaged mitochondria, and mediates mitochondria-lysosome contact, which is critical for lysosomal repair. The role of HKDC1 in maintaining the stability of these organelles counteracts cellular senescence, revealing HKDC1 as a potential therapeutic target for age-related diseases. Just as healthy organs are vital to our well-being, healthy organelles are vital to the proper functioning of the cell. These subcellular structures carry out specific jobs within the cell, for example, mitochondria power the cell and lysosomes keep the cell tidy. Although damage to these two organelles has been linked to aging, cellular senescence, and many diseases, the regulation and maintenance of these organelles has remained poorly understood. Now, researchers at Osaka University have identified a protein, HKDC1, that plays a key role in maintaining these two organelles, thereby acting to prevent cellular aging. There was evidence that a protein called TFEB is involved in maintaining the function of both organelles, but no targets of this protein were known. By comparing all the genes of the cell that are active under particular conditions, and by using a method called chromatin immunoprecipitation, which can identify the DNA targets of proteins, the team were the first to show that the gene encoding HKDC1 is a direct target of TFEB, and that HKDC1 becomes upregulated under conditions of mitochondrial or lysosomal stress. One way that mitochondria are protected from damage is through the process of "mitophagy," the controlled removal of damaged mitochondria. There are various mitophagy pathways, and the most well-characterized of these depends on proteins called PINK1 and Parkin. "We observed that HKDC1 co-localizes with a protein called TOM20, which is located in the outer membrane of the mitochondria," explains lead author Mengying Cui, "and through our experiments, we found that HKDC1, and its interaction with TOM20, are critical for PINK1/Parkin-dependent mitophagy." So, put simply, HKDC1 is brought in by TFEB to help take out the mitochondrial trash. But what about lysosomes? Well, TFEB and KHDC1 are key players here, too. Reducing HKDC1 in the cell was shown to interfere with lysosomal repair, indicating that HKDC1 and TFEB help lysosomes to recover from damage. "HKDC1 is localized to the mitochondria, right? Well, this turns out to also be critical for the process of lysosomal repair," explains senior author Shuhei Nakamura. "You see, lysosomes and mitochondria contact each other via proteins called VDACs. Specifically, HKDC1 is responsible for interacting with the VDACs; this protein is essential for mitochondria-lysosome contact, and thus, lysosomal repair." These two diverse functions of HKDC1, with key roles in both the lysosome and the mitochondria, help to prevent cellular senescence by simultaneously maintaining the stability of these two organelles. As dysfunction of these organelles is linked to aging and age-related diseases, this discovery opens new avenues for therapeutic approaches to these diseases.