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Browsing by Author "Marras, Connie"
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Item A blood-based marker of mitochondrial DNA damage in Parkinson's disease(American Association for the Advancement of Science, 2023) Qi, Rui; Sammler, Esther; Gonzalez-Hunt, Claudia P.; Barraza, Ivana; Pena, Nicholas; Rouanet, Jeremy P.; Naaldijk, Yahaira; Goodson, Steven; Fuzzati, Marie; Blandini, Fabio; Erickson, Kirk I.; Weinstein, Andrea M.; Lutz, Michael W.; Kwok, John B.; Halliday, Glenda M.; Dzamko, Nicolas; Padmanabhan, Shalini; Alcalay, Roy N.; Waters, Cheryl; Hogarth, Penelope; Simuni, Tanya; Smith, Danielle; Marras, Connie; Tonelli, Francesca; Alessi, Dario R.; West, Andrew B.; Shiva, Sruti; Hilfiker, Sabine; Sanders, Laurie H.; Oral and Maxillofacial Surgery and Hospital Dentistry, School of DentistryParkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.Item Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease(Wiley, 2021-07) Lai, Dongbing; Alipanahi, Babak; Fontanillas, Pierre; Schwantes, Tae-Hwi; Aasly, Jan; Alcalay, Roy N.; Beecham, Gary W.; Berg, Daniela; Bressman, Susan; Brice, Alexis; Brockman, Kathrin; Clark, Lorraine; Cookson, Mark; Das, Sayantan; Van Deerlin, Vivianna; Follett, Jordan; Farrer, Matthew J.; Trinh, Joanne; Gasser, Thomas; Goldwurm, Stefano; Gustavsson, Emil; Klein, Christine; Lang, Anthony E.; Langston, J. William; Latourelle, Jeanne; Lynch, Timothy; Marder, Karen; Marras, Connie; Martin, Eden R.; McLean, Cory Y.; Mejia-Santana, Helen; Molho, Eric; Myers, Richard H.; Nuytemans, Karen; Ozelius, Laurie; Payami, Haydeh; Raymond, Deborah; Rogaeva, Ekaterina; Rogers, Michael P.; Ross, Owen A.; Samii, Ali; Saunders-Pullman, Rachel; Schüle, Birgitt; Schulte, Claudia; Scott, William K.; Tanner, Caroline; Tolosa, Eduardo; Tomkins, James E.; Vilas, Dolores; Trojanowski, John Q.; Uitti, Ryan; Vance, Jeffery M.; Visanji, Naomi P.; Wszolek, Zbigniew K.; Zabetian, Cyrus P.; Mirelman, Anat; Giladi, Nir; Urtreger, Avi Orr; Cannon, Paul; Fiske, Brian; Foroud, Tatiana; Medical and Molecular Genetics, School of MedicineObjective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.Item Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study(Oxford University Press, 2024) Westenberger, Ana; Skrahina, Volha; Usnich, Tatiana; Beetz, Christian; Vollstedt, Eva-Juliane; Laabs, Björn-Hergen; Paul, Jefri J.; Curado, Filipa; Skobalj, Snezana; Gaber, Hanaa; Olmedillas, Maria; Bogdanovic, Xenia; Ameziane, Najim; Schell, Nathalie; Aasly, Jan Olav; Afshari, Mitra; Agarwal, Pinky; Aldred, Jason; Alonso-Frech, Fernando; Anderson, Roderick; Araújo, Rui; Arkadir, David; Avenali, Micol; Balal, Mehmet; Benizri, Sandra; Bette, Sagari; Bhatia, Perminder; Bonello, Michael; Braga-Neto, Pedro; Brauneis, Sarah; Costa Cardoso, Francisco Eduardo; Cavallieri, Francesco; Classen, Joseph; Cohen, Lisa; Coletta, Della; Crosiers, David; Cullufi, Paskal; Dashtipour, Khashayar; Demirkiran, Meltem; de Carvalho Aguiar, Patricia; De Rosa, Anna; Djaldetti, Ruth; Dogu, Okan; Dos Santos Ghilardi, Maria Gabriela; Eggers, Carsten; Elibol, Bulent; Ellenbogen, Aaron; Ertan, Sibel; Fabiani, Giorgio; Falkenburger, Björn H.; Farrow, Simon; Fay-Karmon, Tsviya; Ferencz, Gerald J.; Fonoff, Erich Talamoni; Fragoso, Yara Dadalti; Genç, Gençer; Gorospe, Arantza; Grandas, Francisco; Gruber, Doreen; Gudesblatt, Mark; Gurevich, Tanya; Hagenah, Johann; Hanagasi, Hasmet A.; Hassin-Baer, Sharon; Hauser, Robert A.; Hernández-Vara, Jorge; Herting, Birgit; Hinson, Vanessa K.; Hogg, Elliot; Hu, Michele T.; Hummelgen, Eduardo; Hussey, Kelly; Infante, Jon; Isaacson, Stuart H.; Jauma, Serge; Koleva-Alazeh, Natalia; Kuhlenbäumer, Gregor; Kühn, Andrea; Litvan, Irene; López-Manzanares, Lydia; Luxmore, McKenzie; Manandhar, Sujeena; Marcaud, Veronique; Markopoulou, Katerina; Marras, Connie; McKenzie, Mark; Matarazzo, Michele; Merello, Marcelo; Mollenhauer, Brit; Morgan, John C.; Mullin, Stephen; Musacchio, Thomas; Myers, Bennett; Negrotti, Anna; Nieves, Anette; Nitsan, Zeev; Oskooilar, Nader; Öztop-Çakmak, Özgür; Pal, Gian; Pavese, Nicola; Percesepe, Antonio; Piccoli, Tommaso; Pinto de Souza, Carolina; Prell, Tino; Pulera, Mark; Raw, Jason; Reetz, Kathrin; Reiner, Johnathan; Rosenberg, David; Ruiz-Lopez, Marta; Ruiz Martinez, Javier; Sammler, Esther; Santos-Lobato, Bruno Lopes; Saunders-Pullman, Rachel; Schlesinger, Ilana; Schofield, Christine M.; Schumacher-Schuh, Artur F.; Scott, Burton; Sesar, Ángel; Shafer, Stuart J.; Sheridan, Ray; Silverdale, Monty; Sophia, Rani; Spitz, Mariana; Stathis, Pantelis; Stocchi, Fabrizio; Tagliati, Michele; Tai, Yen F.; Terwecoren, Annelies; Thonke, Sven; Tönges, Lars; Toschi, Giulia; Tumas, Vitor; Urban, Peter Paul; Vacca, Laura; Vandenberghe, Wim; Valente, Enza Maria; Valzania, Franco; Vela-Desojo, Lydia; Weill, Caroline; Weise, David; Wojcieszek, Joanne; Wolz, Martin; Yahalom, Gilad; Yalcin-Cakmakli, Gul; Zittel, Simone; Zlotnik, Yair; Kandaswamy, Krishna K.; Balck, Alexander; Hanssen, Henrike; Borsche, Max; Lange, Lara M.; Csoti, Ilona; Lohmann, Katja; Kasten, Meike; Brüggemann, Norbert; Rolfs, Arndt; Klein, Christine; Bauer, Peter; Neurology, School of MedicineEstimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.