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2. Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case–control study

Author

Ross, Owen A, Soto-Ortolaza, Alexandra I, Heckman, Michael G, Aasly, Jan O, Abahuni, Nadine, Annesi, Grazia, Bacon, Justin A, Bardien, Soraya, Bozi, Maria, Brice, Alexis, Brighina, Laura, Van Broeckhoven, Christine, Carr, Jonathan, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Dickson, Dennis W, Diehl, Nancy N, Elbaz, Alexis, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gibson, J Mark, Gibson, Rachel, Hadjigeorgiou, Georgios M, Hattori, Nobutaka, Ioannidis, John PA, Jasinska-Myga, Barbara, Jeon, Beom S, Kim, Yun Joong, Klein, Christine, Kruger, Rejko, Kyratzi, Elli, Lesage, Suzanne, Lin, Chin-Hsien, Lynch, Timothy, Maraganore, Demetrius M, Mellick, George D, Mutez, Eugénie, Nilsson, Christer, Opala, Grzegorz, Park, Sung Sup, Puschmann, Andreas, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A, Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Tomiyama, Hiroyuki, Uitti, Ryan J, Valente, Enza Maria, van de Loo, Simone, Vassilatis, Demetrios K, Vilariño-Güell, Carles, White, Linda R, Wirdefeldt, Karin, Wszolek, Zbigniew K, Wu, Ruey-Meei, and Farrer, Matthew J

Published
2011
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3. Population-specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinsonʼs disease (GEO-PD) consortium

Author

Heckman, Michael G., Soto-Ortolaza, Alexandra I., Aasly, Jan O., 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., Elbaz, Alexis, Ferrarese, Carlo, Fiske, Brian, Gibson, Mark J., Gibson, Rachel, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P.A., Boczarska-Jedynak, Magdalena, Jasinska-Myga, Barbara, Jeon, Beom S., Kim, Yun Joong, Klein, Christine, Kruger, Rejko, Kyratzi, Elli, Lesage, Suzanne, Lin, Chin-Hsien, Lynch, Timothy, Maraganore, Demetrius M., Mellick, George D., Mutez, Eugénie, Nilsson, Christer, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Puschmann, Andreas, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, Van Broeckhoven, Christine, van de Loo, Simone, Vassilatis, Demetrios K., Vilariño-Güell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Hentati, Faycal, Farrer, Matthew J., and Ross, Owen A.

Published
2013
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5. The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Author

Heckman, Michael G., Elbaz, Alexis, Soto-Ortolaza, Alexandra I., Serie, Daniel J., Aasly, Jan O., Annesi, Grazia, Auburger, Georg, Bacon, Justin A., Boczarska-Jedynak, Magdalena, Bozi, Maria, Brighina, Laura, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Destée, Alain, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gispert, Suzana, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P.A., Jasinska-Myga, Barbara, Jeon, Beom S., Kim, Yun Joong, Klein, Christine, Kruger, Rejko, Kyratzi, Elli, Lin, Chin-Hsien, Lohmann, Katja, Loriot, Marie-Anne, Lynch, Timothy, Mellick, George D., Mutez, Eugénie, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, Vassilatis, Demetrios K., Vilariño-Güell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Xiromerisiou, Georgia, Maraganore, Demetrius M., Farrer, Matthew J., and Ross, Owen A.

Published
2014
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9. Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Author

Heckman, Michael G, Elbaz, Alexis, Brighina, Laura, Pastor, Pao, Payami, Haydeh, Pchelina, Sofya N, Petersen, Maria Skaalum, Puschmann, Andrea, Ritz, Beate, Rogaeva, Ekaterina, Sazci, Ali, Slawek, Jaroslaw, Stefanis, Leonidas, Chartier-Harlin, Marie-Christine, Tan, Eng-King, Toda, Tatsushi, Toft, Mathias, Van Broeckhoven, Christine, Wirdefeldt, Karin, Woitalla, Dirk, Wszolek, Zbigniew K, Zimprich, Alexander, Dardiotis, Efthimios, Destée, Alain, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gispert, Suzana, Hadjigeorgiou, Georgios M, Hattori, Nobutaka, Soto-Ortolaza, Alexandra I, Ioannidis, John P A, Jasinska-Myga, Barbara, Jeon, Beom S, Kim, Yun Joong, Klein, Christine, Kruger, Rejko, Kyratzi, Elli, Lin, Chin-Hsien, Lohmann, Katja, Loriot, Marie-Anne, Serie, Daniel J, Lynch, Timothy, Mellick, George D, Mutez, Eugénie, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A, Sohn, Young Ho, Aasly, Jan O, Tadic, Vera, Tomiyama, Hiroyuki, Uitti, Ryan J, Valente, Enza Maria, Vassilatis, Demetrios K, Vilariño-Güell, Carles, White, Linda R, Annesi, Grazia, Wu, Ruey-Meei, Xiromerisiou, Georgia, Maraganore, Demetrius M, Farrer, Matthew J, Ross, Owen A, Disease, Genetic Epidemiology Of Parkinson's, Auburger, Georg, Ioannidis, John P, Annesi, Grazie, Bentivoglio, Annarita, Bozi, Maria, Brice, Alexis, Carmine-Belin, Andrea, Carr, Jonathan, Bacon, Justin A, Carroll, Camille, Chase, Bruce, Checkoway, Harvey, Chen, Sheng-Di, Chung, Sun Ju, Cosentino, Carlos, Cresswell, Silke, Deutschlaender, Angela, Boczarska-Jedynak, Magdalena, Foroud, Tatiana, Garraux, Gaëtan, Goldwurm, Stefano, Hadjigeorgiou, George, Jeon, Beom Seok, Kawakami, Hideshi, Kishore, Asha, Krainc, Dimitri, Krygowska-Wajs, Anna, Lay-Son, Luis, Lin, Jeui-Jueng, Mellick, George, Morrison, Karen E, Munhoz, Renato P, Okubadejo, Njide U, Van Broeckhoven, Christine, Heckman, M, Elbaz, A, Soto Ortolaza, A, Serie, D, Aasly, J, Annesi, G, Auburger, G, Bacon, J, Boczarska Jedynak, M, Bozi, M, Brighina, L, Chartier Harlin, M, Dardiotis, E, Destée, A, Ferrarese, C, Ferraris, A, Fiske, B, Gispert, S, Hadjigeorgiou, G, Hattori, N, Ioannidis, J, Jasinska Myga, B, Jeon, B, Kim, Y, Klein, C, Kruger, R, Kyratzi, E, Lin, C, Lohmann, K, Loriot, M, Lynch, T, Mellick, G, Mutez, E, Opala, G, Park, S, Petrucci, S, Quattrone, A, Sharma, M, Silburn, P, Sohn, Y, Stefanis, L, Tadic, V, Tomiyama, H, Uitti, R, Valente, E, Vassilatis, D, Vilariño Güell, C, White, L, Wirdefeldt, K, Wszolek, Z, Wu, R, Xiromerisiou, G, Maraganore, D, Farrer, M, and Ross, O

Subjects
Male, Aging, Parkinson's disease, european continental ancestry group, chemistry.chemical_compound, genetics [Parkinson Disease], Genotype, 80 and over, MAPT, genetics, genetics [Genetic Predisposition to Disease], Genetics, Aged, 80 and over, biology, General Neuroscience, LRRK2, Parkinson Disease, Middle Aged, Protein-Serine-Threonine Kinases, genetics [European Continental Ancestry Group], genetics [alpha-Synuclein], alpha-Synuclein, Medical genetics, Female, interaction, lrrk2, mapt, parkinson's disease, snca, adolescent, adult, aged, aged, 80 and over, asian continental ancestry group, female, genetic predisposition to disease, genotype, haplotypes, humans, leucine-rich repeat serine-threonine protein kinase-2, male, middle aged, parkinson disease, protein-serine-threonine kinases, risk, young adult, alpha-synuclein, tau proteins, genetic variation, Adult, Risk, medicine.medical_specialty, Interaction, Adolescent, Tau protein, MAPT protein, human, tau Proteins, Protein Serine-Threonine Kinases, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, genetics [Protein-Serine-Threonine Kinases], White People, Article, Young Adult, Genetic, Asian People, Genetic variation, genetics [Haplotypes], medicine, Humans, Genetic Predisposition to Disease, ddc:610, LRRK2 protein, human, SNCA protein, human, Biology, Aged, Alpha-synuclein, genetics [Asian Continental Ancestry Group], Haplotype, Genetic Variation, medicine.disease, nervous system diseases, genetics [tau Proteins], Haplotypes, chemistry, biology.protein, prevention & control [Parkinson Disease], SNCA, Neurology (clinical), Human medicine, Geriatrics and Gerontology, Developmental Biology
Abstract

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotypedefining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

Published
2014

12. Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Heckman, Michael G., Elbaz, Alexis, Soto-Ortolaza, Alexandra I., Serie, Daniel J., Aasly, Jan O., Annesi, Grazia, Auburger, Georg, Bacon, Justin A., Boczarska-Jedynak, Magdalena, Bozi, Maria, Brighina, Laura, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Destee, Alain, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gispert, Suzana, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P. A., Jasinska-Myga, Barbara, Jeon, Beom S., Kim, Yun Joong, Klein, Christine, Krüger, Rejko, Kyratzi, Elli, Lin, Chin-Hsien, Lohmann, Katja, Loriot, Marie-Anne, Lynch, Timothy, Mellick, George D., Mutez, Eugenie, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, Vassilatis, Demetrios K., Vilarino-Guell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Xiromerisiou, Georgia, Maraganore, Demetrius M., Farrer, Matthew J., Ross, Owen A., Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Heckman, Michael G., Elbaz, Alexis, Soto-Ortolaza, Alexandra I., Serie, Daniel J., Aasly, Jan O., Annesi, Grazia, Auburger, Georg, Bacon, Justin A., Boczarska-Jedynak, Magdalena, Bozi, Maria, Brighina, Laura, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Destee, Alain, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gispert, Suzana, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P. A., Jasinska-Myga, Barbara, Jeon, Beom S., Kim, Yun Joong, Klein, Christine, Krüger, Rejko, Kyratzi, Elli, Lin, Chin-Hsien, Lohmann, Katja, Loriot, Marie-Anne, Lynch, Timothy, Mellick, George D., Mutez, Eugenie, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, Vassilatis, Demetrios K., Vilarino-Guell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Xiromerisiou, Georgia, Maraganore, Demetrius M., Farrer, Matthew J., and Ross, Owen A.

Abstract

The best validated susceptibility variants for Parkinson's disease are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p >/= 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

Published
2014
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13. The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells

Author

Kyratzi, Elli Pavlaki, Maria Stefanis, Leonidas

Abstract

A number of studies have associated the S18Y polymorphic variant of UCH-L1 with protection from sporadic Parkinson’s Disease (PD). The mechanism involved in this protective function is unknown, but has generally been assumed to be linked to the ubiquitin-proteasome system (UPS). In the current study, we have investigated the effects of overexpression of UCH-L1 and its variants, including S18Y, in neuronal cells. We find that S18Y, but not WT, UCH-L1 confers a specific antioxidant protective function when expressed at physiological levels in human neuroblastoma cells and primary cortical neurons. In contrast, neither WT nor S18Y UCH-L1 appear to directly impact the proteasome, although they both lead to stabilization of free ubiquitin. Lack of WT mouse UCH-L1 in neurons derived from gad mice led to a decrease of free ubiquitin, but no overall decrease in UPS function or enhanced sensitivity to oxidative stress. We conclude that the S18Y variant of UCH-L1 confers a novel antioxidant function that is not present in the WT form and that this function may underlie the protective effects of this variant in certain PD populations. Our results furthermore provide indirect evidence for the importance of oxidative stress as a pathogenetic factor in certain forms of sporadic PD.

Published
2008

15. Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Heckman, Michael G., Soto-Ortolaza, Alexandra I., Aasly, Jan O., 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., Elbaz, Alexis, Ferrarese, Carlo, Fiske, Brian, Gibson, J. Mark, Gibson, Rachel, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P. A., Boczarska-Jedynak, Magdalena, Jasinska-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, Eugenie, Nilsson, Christer, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Puschmann, Andreas, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, Van Broeckhoven, Christine, van de Loo, Simone, Vassilatis, Demetrios K., Vilarino-Guell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Hentati, Faycal, Farrer, Matthew J., Ross, Owen A., Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Heckman, Michael G., Soto-Ortolaza, Alexandra I., Aasly, Jan O., 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., Elbaz, Alexis, Ferrarese, Carlo, Fiske, Brian, Gibson, J. Mark, Gibson, Rachel, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P. A., Boczarska-Jedynak, Magdalena, Jasinska-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, Eugenie, Nilsson, Christer, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Puschmann, Andreas, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, Van Broeckhoven, Christine, van de Loo, Simone, Vassilatis, Demetrios K., Vilarino-Guell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Hentati, Faycal, Farrer, Matthew J., and Ross, Owen A.

Abstract

BACKGROUND: Variants 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. METHODS: The 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. RESULTS: Herein, 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. CONCLUSIONS: Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies.

Published
2013

16. Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Ross, Owen A., Soto-Ortolaza, Alexandra I., Heckman, Michael G., Aasly, Jan O., Abahuni, Nadine, Annesi, Grazia, Bacon, Justin A., Bardien, Soraya, Bozi, Maria, Brice, Alexis, Brighina, Laura, Van Broeckhoven, Christine, Carr, Jonathan, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Dickson, Dennis W., Diehl, Nancy N., Elbaz, Alexis, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gibson, J. Mark, Gibson, Rachel, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P. A., Jasinska-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, Eugenie, Nilsson, Christer, Opala, Grzegorz, Park, Sung Sup, Puschmann, Andreas, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, van de Loo, Simone, Vassilatis, Demetrios K., Vilarino-Guell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Farrer, Matthew J., Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Ross, Owen A., Soto-Ortolaza, Alexandra I., Heckman, Michael G., Aasly, Jan O., Abahuni, Nadine, Annesi, Grazia, Bacon, Justin A., Bardien, Soraya, Bozi, Maria, Brice, Alexis, Brighina, Laura, Van Broeckhoven, Christine, Carr, Jonathan, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Dickson, Dennis W., Diehl, Nancy N., Elbaz, Alexis, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gibson, J. Mark, Gibson, Rachel, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P. A., Jasinska-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, Eugenie, Nilsson, Christer, Opala, Grzegorz, Park, Sung Sup, Puschmann, Andreas, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, van de Loo, Simone, Vassilatis, Demetrios K., Vilarino-Guell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, and Farrer, Matthew J.

Abstract

BACKGROUND: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS: LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS: 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk associati

Published
2011
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18. Selective neuroprotective effects of the S18Y polymorphic variant of UCH-L1 in the dopaminergic system

Author

Xilouri, Maria, primary, Kyratzi, Elli, additional, Pitychoutis, Pothitos M., additional, Papadopoulou-Daifoti, Zoi, additional, Perier, Celine, additional, Vila, Miquel, additional, Maniati, Matina, additional, Ulusoy, Ayse, additional, Kirik, Deniz, additional, Park, David S., additional, Wada, Keiji, additional, and Stefanis, Leonidas, additional

Published
2011
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19. Stress, the stress system and the role of glucocorticoids.

Author

Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, and Charmandari E

Subjects
Animals, Humans, Glucocorticoids metabolism, Hypothalamo-Hypophyseal System metabolism, Pituitary-Adrenal System metabolism, Stress, Psychological metabolism, Stress, Psychological pathology
Abstract

All living organisms have developed a highly conserved and regulatory system, the stress system, to cope with a broad spectrum of stressful stimuli that threaten, or are perceived as threatening, their dynamic equilibrium or homeostasis. This neuroendocrine system consists of the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-autonomic nervous system. In parallel with the evolution of the homeostasis and stress concepts from ancient Greek to modern medicine, significant advances in the field of neuroendocrinology have identified the physiologic biochemical effector molecules of the stress response. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome. This review describes the central and peripheral components of the stress system, provides a comprehensive overview of the stress response, and discusses the role of glucocorticoids in a broad spectrum of stress-related diseases. © 2014 S. Karger AG, Basel.

Published
2015
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20. Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants.

Author

Heckman MG, Elbaz A, Soto-Ortolaza AI, Serie DJ, Aasly JO, Annesi G, Auburger G, Bacon JA, Boczarska-Jedynak M, Bozi M, Brighina L, Chartier-Harlin MC, Dardiotis E, Destée A, Ferrarese C, Ferraris A, Fiske B, Gispert S, Hadjigeorgiou GM, Hattori N, Ioannidis JP, Jasinska-Myga B, Jeon BS, Kim YJ, Klein C, Kruger R, Kyratzi E, Lin CH, Lohmann K, Loriot MA, Lynch T, Mellick GD, Mutez E, Opala G, Park SS, Petrucci S, Quattrone A, Sharma M, Silburn PA, Sohn YH, Stefanis L, Tadic V, Tomiyama H, Uitti RJ, Valente EM, Vassilatis DK, Vilariño-Güell C, White LR, Wirdefeldt K, Wszolek ZK, Wu RM, Xiromerisiou G, Maraganore DM, Farrer MJ, and Ross OA

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Asian People genetics, Female, Genotype, Haplotypes genetics, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Risk, White People genetics, Young Adult, Genetic Predisposition to Disease genetics, Genetic Variation, Parkinson Disease genetics, Parkinson Disease prevention & control, Protein Serine-Threonine Kinases genetics, alpha-Synuclein genetics, tau Proteins genetics
Abstract

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Published
2014
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