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5. Functional variants in the LRRK2 gene confer shared effects on risk for Crohns disease and Parkinsons disease.

Author

Hui, Ken, Fernandez-Hernandez, Heriberto, Hu, Jianzhong, Schaffner, Adam, Pankratz, Nathan, Hsu, Nai-Yun, Chuang, Ling-Shiang, Carmi, Shai, Villaverde, Nicole, Li, Xianting, Rivas, Manual, Levine, Adam, Bao, Xiuliang, Labrias, Philippe, Haritunians, Talin, Ruane, Darren, Gettler, Kyle, Chen, Ernie, Li, Dalin, Schiff, Elena, Pontikos, Nikolas, Barzilai, Nir, Brant, Steven, Bressman, Susan, Cheifetz, Adam, Clark, Lorraine, Daly, Mark, Desnick, Robert, Duerr, Richard, Katz, Seymour, Lencz, Todd, Myers, Richard, Ostrer, Harry, Ozelius, Laurie, Payami, Haydeh, Peter, Yakov, Rioux, John, Segal, Anthony, Scott, William, Silverberg, Mark, Vance, Jeffery, Ubarretxena-Belandia, Iban, Foroud, Tatiana, Atzmon, Gil, Peer, Itsik, Ioannou, Yiannis, McGovern, Dermot, Yue, Zhenyu, Schadt, Eric, Cho, Judy, and Peter, Inga

Subjects
Alleles, Autophagy, Crohn Disease, Cytoskeleton, Exome, Gene Frequency, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Macrophages, Odds Ratio, Open Reading Frames, Parkinson Disease, Phenotype, Reproducibility of Results, Risk Factors, Exome Sequencing
Abstract

Crohns disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10-10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10-8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinsons disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.

Published
2018

10. Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Author

Schaffner, Adam, Li, Xianting, Gomez-Llorente, Yacob, Leandrou, Emmanouela, Memou, Anna, Clemente, Nicolina, Yao, Chen, Afsari, Farinaz, Zhi, Lianteng, Pan, Nina, Morohashi, Keita, Hua, Xiaoluan, Zhou, Ming-Ming, Wang, Chunyu, Zhang, Hui, Chen, Shu G., Elliott, Christopher J., Rideout, Hardy, Ubarretxena-Belandia, Iban, and Yue, Zhenyu

Published
2019
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14. Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

Author

Guaitoli, Giambattista, Raimondi, Francesco, Gilsbach, Bernd K., Gómez-Llorente, Yacob, Deyaert, Egon, Renzi, Fabiana, Li, Xianting, Schaffner, Adam, Jagtap, Pravin Kumar Ankush, Boldt, Karsten, von Zweydorf, Felix, Gotthardt, Katja, Lorimer, Donald D., Yue, Zhenyu, Burgin, Alex, Janjic, Nebojsa, Sattler, Michael, Versées, Wim, Ueffing, Marius, Ubarretxena-Belandia, Iban, Kortholt, Arjan, and Gloeckner, Christian Johannes

Published
2016

25. Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor

Author

Al Rahim, Md, primary, Yoon, Yonejung, additional, Dimovasili, Christina, additional, Shao, Zhiping, additional, Huang, Qian, additional, Zhang, Emily, additional, Kezunovic, Nebojsa, additional, Chen, Lei, additional, Schaffner, Adam, additional, Huntley, George W, additional, Ubarretxena-Belandia, Iban, additional, Georgakopoulos, Anastasios, additional, and Robakis, Nikolaos K, additional

Published
2020
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28. Vitamin B12modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Author

Schaffner, Adam, Li, Xianting, Gomez-Llorente, Yacob, Leandrou, Emmanouela, Memou, Anna, Clemente, Nicolina, Yao, Chen, Afsari, Farinaz, Zhi, Lianteng, Pan, Nina, Morohashi, Keita, Hua, Xiaoluan, Zhou, Ming-Ming, Wang, Chunyu, Zhang, Hui, Chen, Shu G., Elliott, Christopher J., Rideout, Hardy, Ubarretxena-Belandia, Iban, and Yue, Zhenyu

Abstract

Missense mutations in Leucine-Rich Repeat Kinase 2(LRRK2) cause the majority of familial and some sporadic forms of Parkinson’s disease (PD). The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity, promoting the development of LRRK2 kinase inhibitors as therapeutics. Many potent and specific small-molecule LRRK2 inhibitors have been reported with promise. However, nearly all inhibitors are ATP competitive—some with unwanted side effects and unclear clinical outcome—alternative types of LRRK2 inhibitors are lacking. Herein we identify 5′-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B12as a mixed-type allosteric inhibitor of LRRK2 kinase activity. Multiple assays show that AdoCbl directly binds LRRK2, leading to the alterations of protein conformation and ATP binding in LRRK2. STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain. Furthermore, we provide evidence that AdoCbl modulates LRRK2 activity through disrupting LRRK2 dimerization. Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue, and prevents neurotoxicity in cultured primary rodent neurons as well as in transgenic C. elegansand D. melanogasterexpressing LRRK2 disease variants. Finally, AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models. Our study uncovers vitamin B12as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the future.

Published
2019
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30. G protein Gating of a Kir3.1-Prokaryotic Kir Channel Chimera Functionally Reconstituted in Planar Lipid Bilayers

Author

Leal-Pinto, Edgar, primary, Gómez-Llorente, Yacob, additional, Sundaram, Shobana, additional, Tang, Qiong-Yao, additional, Ivanova-Nikolova, Tatyana, additional, Mahajan, Rahul, additional, Baki, Lia, additional, Zhang, Zhe, additional, Chavez, Jose, additional, Ubarretxena-Belandia, Iban, additional, and Logothetis, Diomedes E., additional

Published
2011
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34. Inward-facing conformation of the zinc transporter YiiP revealed by cryoelectron microscopy.

Author

Coudraya, Nicolas, Valvo, Salvatore, Hua, Minghui, Lasala, Ralph, Kim, Changki, Vink, Martin, Zhou, Ming, Provasi, Davide, Filizola, Marta, Tao, Juoehi, Jia Fang, Penczek, Pawel A., Ubarretxena-Belandia, Iban, and Stokes, David L.

Subjects
BILAYER lipid membranes, MEMBRANE proteins, MOLECULAR dynamics, METAL ions, X-ray crystallography, ELECTRON cryomicroscopy
Abstract

YiiP is a dimeric Zn2+/H+ antiporter from Eacherichia coil belonging to the cation diffusion facilitator family. We used cryoelectron microscopy to determine a 13-Å resolution structure of a YiiP homolog from Shewaneiia oneidensis within a lipid bilayer in the absence of Zn2+ Starting from the X-ray structure in the presence of Zn2+, we used molecular dynamics flexible fitting to build a model consistent with our map. Comparison of the structures suggests a conforma- tional change that involves pivoting of a transmembrane, four-helix bundle (M1, M2, M4, and M5) relative to the M3-M6 helix pair. Although accessibility of transport sites in the X-ray model indicates that it represents an outward-facing state, our model is consistent with an inward-facing state, suggesting that the conformational change is relevant to the alternating access mechanism for transport. Molecular dynamics simulation of YiiP in a lipid environment was used to address the feasibility of this conformational change. Association of the C-terminal domains is the same in both states, and we speculate that this association is responsible for stabilizing the dimer that in turn. may coordinate the rearrangement of the trans- membrane helices. [ABSTRACT FROM AUTHOR]

Published
2013
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