Carr, Jonathan
Mayo Clinic
Tygerberg Hospital and University of Stellenbosch, Tygerberg 7505, South Africa.
Citations 2
Modeling Lewy body disease with SNCA triplication iPSC-derived cortical organoids and identifying therapeutic drugs
Jin, Yunjung , Li, Fuyao , Li, Zonghua , Ikezu, Tadafumi C. , O’Leary, Justin , Selvaraj, Manikandan , Zhu, Yiyang , Martens, Yuka A. , Koga, Shunsuke , Santhakumar, Hannah , Li, Yonghe , Lü, Wenyan, You, Yang , Lolo, Kiara , DeTure, Michael , Davis, Mary Dabney , McLean, Pamela J. , Ross, Owen A. , Kanekiyo, Takahisa , Zhao, Na , Beasley, Alexandra I , Davis, Mary D , McLean, Pamela J , Ross, Owen A , Kanekiyo, Takahisa , Ikezu, Tsuneya , Caulfield, Thomas R , Carr, Jonathan , Wszolek, Z.K. , Bu, Guojun , Dickson, Dennis W , Zhao, Na , Koga, Shunsuke , Li, Zonghua , Li, Fuyao , Yang, You , Soto‐Beasley, Alexandra I. , Ikezu, Tsuneya , Caulfield, Thomas R. , Carr, Jonathan , Wszołek, Zbigniew K. , Bu, Guojun , Dickson, Dennis W.
Science Advances | September 11, 2024 | Volume: 10 | Issue: 37 | Pages: No page available
Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)–derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration–approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.
Population‐specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO‐PD) consortium
Soto‐Ortolaza, Alexandra I., Aasly, Jan , Abahuni, Nadine, Annesi, Grazia , Bacon, Justin A., Bardien, Soraya , Bozi, Maria , Brice, Alexis , Brighina, Laura , Carr, Jonathan , Chartier‐Harlin, Marie‐Christine , Dardiotis, Efthimios , Dickson, Dennis W. , Diehl, Nancy N. , Ferrarese, Carlo , Fiske, Brian , Gibson, Rachel A. , Hattori, Nobutaka , Ioannidis, John P. A. , Boczarska‐Jedynak, Magdalena , Jasińska‐Myga, Barbara, Jeon, Beom S., Kim, Yun Joong , Klein, Christine , Krüger, Rejko , Kyratzi, Elli, Lesage, Suzanne , Lin, Chin‐Hsien , Lynch, Timothy , Maraganore, Demetrius M. , Mellick, George D. , Mutez, Eugénie , Opala, Grzegorz, Park, Sung Sup , Petrucci, Simona , Puschmann, Andreas , Quattrone, Aldo , Sharma, Manu , Silburn, Peter A., Sohn, Young H. , Tadić, Vera, Theuns, Jessie , Tomiyama, Hiroyuki , Uitti, Ryan J. , Valente, Enza Maria , Broeckhoven, Christine Van , Loo, Simone van de, Vassilatis, Demetrios K. , Vilariño‐Güell, Carles , White, Linda R., Wirdefeldt, Karin , Wu, Ruey‐Meei , Hentati, Fayçal, Farrer, Matthew J. , Ross, Owen A. , Soto‐Beasley, Alexandra I. , Heckman, Michael G. , Elbaz, Alexis , Gibson, Jonathan M. , Hadjigeorgiou, Georgios M. , Nilsson, Christer C. , Stefanis, Leonidas , Wszołek, Zbigniew K. , Dickson, Dennis W , Ross, Owen A , Puschmann, Andreas , Klein, Christine , Bardien, Soraya , Mutez, Eugénie , Valente, Enza Maria , Ioannidis, John P A , Beasley, Alexandra I , Carr, Jonathan , Brice, Alexis , Lin, Chin-Hsien , Wu, Ruey-Meei
Movement Disorders | August 2, 2013 | Volume: 28 | Issue: 12 | Pages: 1740-1744
ABSTRACTBackgroundVariants within the leucine‐rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine‐rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late‐onset sporadic disorders like Parkinson's disease.MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine‐rich repeat kinase 2 gene across 23 different sites in 15 countries.ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K‐R1398H‐K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.ConclusionsEstablishing individual patient‐based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 International Parkinson and Movement Disorder Society