On genes involved in common neurological disorders : focus on Parkinson's disease
Author: Ran, Caroline
Date: 2014-10-03
Location: Föreläsningssal Hillarp, Retzius väg 8, Karolinska Institutet, Solna.
Time: 09:00
Department: Inst för neurovetenskap / Dept of Neuroscience
Abstract
Parkinson’s disease and migraine are complex neurological disorders and it is likely that a combination of genetic risk factors are involved in the etiology of both these diseases. Papers in this thesis investigate candidate genes in the search of genetic risk factors contributing to disease.
Genetic research on Parkinson’s disease is extensive. Therefore, genes belonging to certain groups of risk-genes that are particularly interesting with regard to their function were selected for investigation in relation to this disease. We have performed association analyses alongside with gene expression and behavioral studies. Genetic variations in genes encoding detoxifying enzymes and genes involved in cellular processes of cell protection and survival have received special focus. We have also studied genes involved in mitochondrial function and genes linked to rare forms of hereditary Parkinson’s disease. A more recent approach in genetic studies has been to investigate genes shown to associate with or have close to significant p-values in genome wide association studies. In line with this, we have investigated major histocompability complex class II DR alpha (HLA-DRA), a gene connected to the immune-response, in our well characterized Parkinson’s disease case-control material.
Through genetic analysis we have found evidence supportive of paraoxonase (PON) 1 and 2, mitochondrial translation initiation factor 3 (MTIF3), nuclear factor erythroid 2-like 2 (NRF2) and glucocerebrosidase (GBA) being associated with Parkinson’s disease. One single nucleotide polymorphism (SNP) in PON1 was associated with decreased risk of disease, while the other three genes were found to harbor SNPs and mutations conferring increased risk of Parkinson’s disease. The SNP in MTIF3 represents an expression quantitative trait locus and the presence of the minor allele was accompanied by a decrease in mRNA levels. Mitochondrial Ras homolog family (MIRO) 1 and 2, v-akt murine thymoma viral oncogene homolog 1 (AKT1) and HLA-DRA were also investigated, and shown not to associate with disease in our material. In spite of the lack of association with AKT1, we discovered that Parkinson patients had lower AKT1 gene expression, which we interpreted as a consequence of the constituent pathological conditions. We also studied alcohol dehydrogenase (ADH) genes and leucine-rich repeat kinase 2 (LRRK2) in animal models of Parkinson’s disease. We discovered that Lrrk2 and α-synuclein were co-regulated in the rodent striatum and that the lack of dopamine itself did not seem to influence the expression of these genes. In contrast, we found that absence of ADH genes, which are not expressed in the brain, could influence dopamine-dependent behavior in mice. Taken together, we have found evidence of involvement of all the targeted pathways and familial PD genes, with the exception of the immunological gene HLA-DRA.
Little is known about the genetic relationships that might cause or influence the risk of migraine. Therefore we aimed to validate previously published genetic findings using microarray data in a well characterized Swedish cohort. Our study supports the involvement of genetic factors in migraine. We analyzed SNPs in eight candidate genes for migraine and our data are in favor of one SNP in PR domain containing 16 (PRDM16) and one SNP in the proximity of metadherin (MTDH) as risk factors for migraine in Sweden.
Genetic research on Parkinson’s disease is extensive. Therefore, genes belonging to certain groups of risk-genes that are particularly interesting with regard to their function were selected for investigation in relation to this disease. We have performed association analyses alongside with gene expression and behavioral studies. Genetic variations in genes encoding detoxifying enzymes and genes involved in cellular processes of cell protection and survival have received special focus. We have also studied genes involved in mitochondrial function and genes linked to rare forms of hereditary Parkinson’s disease. A more recent approach in genetic studies has been to investigate genes shown to associate with or have close to significant p-values in genome wide association studies. In line with this, we have investigated major histocompability complex class II DR alpha (HLA-DRA), a gene connected to the immune-response, in our well characterized Parkinson’s disease case-control material.
Through genetic analysis we have found evidence supportive of paraoxonase (PON) 1 and 2, mitochondrial translation initiation factor 3 (MTIF3), nuclear factor erythroid 2-like 2 (NRF2) and glucocerebrosidase (GBA) being associated with Parkinson’s disease. One single nucleotide polymorphism (SNP) in PON1 was associated with decreased risk of disease, while the other three genes were found to harbor SNPs and mutations conferring increased risk of Parkinson’s disease. The SNP in MTIF3 represents an expression quantitative trait locus and the presence of the minor allele was accompanied by a decrease in mRNA levels. Mitochondrial Ras homolog family (MIRO) 1 and 2, v-akt murine thymoma viral oncogene homolog 1 (AKT1) and HLA-DRA were also investigated, and shown not to associate with disease in our material. In spite of the lack of association with AKT1, we discovered that Parkinson patients had lower AKT1 gene expression, which we interpreted as a consequence of the constituent pathological conditions. We also studied alcohol dehydrogenase (ADH) genes and leucine-rich repeat kinase 2 (LRRK2) in animal models of Parkinson’s disease. We discovered that Lrrk2 and α-synuclein were co-regulated in the rodent striatum and that the lack of dopamine itself did not seem to influence the expression of these genes. In contrast, we found that absence of ADH genes, which are not expressed in the brain, could influence dopamine-dependent behavior in mice. Taken together, we have found evidence of involvement of all the targeted pathways and familial PD genes, with the exception of the immunological gene HLA-DRA.
Little is known about the genetic relationships that might cause or influence the risk of migraine. Therefore we aimed to validate previously published genetic findings using microarray data in a well characterized Swedish cohort. Our study supports the involvement of genetic factors in migraine. We analyzed SNPs in eight candidate genes for migraine and our data are in favor of one SNP in PR domain containing 16 (PRDM16) and one SNP in the proximity of metadherin (MTDH) as risk factors for migraine in Sweden.
List of papers:
I. Anvret A, Ran C, Westerlund M, Gellhaar S, Lindqvist E, Pernold K, Lundströmer K, Duester G, Felder M.R, Galter D, Belin AC. Adh1 and Adh1/4 knockout mice as possible rodent models for presymptomatic Parkinson's disease. Behav Brain Res. 227, 252-257, 2012.
Fulltext (DOI)
Pubmed
II. Belin AC, Ran C, Anvret A, Paddock S, Westerlund M, Håkansson A, Nissbrandt H, Söderkvist P, Dizdar N, Ahmadi A, Anvret M, Willows T, Sydow O, Galter D. Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease. Neurosci Lett. 522, 30-35, 2012.
Fulltext (DOI)
Pubmed
III. Anvret A, Ran C, Westerlund M, Thelander AC, Sydow O, Lind C, Håkansson A, Nissbrandt H, Galter D, Belin AC. Possible Involvement of a Mitochondrial Translation Initiation Factor 3 Variant Causing Decreased mRNA Levels in Parkinson's disease. Parkinsons Dis. 2010, Article ID 491751, 2010.
Fulltext (DOI)
Pubmed
IV. Anvret A, Ran C, Westerlund M, Sydow O, Willows T, Olson L, Galter D, Belin AC. Genetic Screening of the Mitochondrial Rho GTPases MIRO1 and MIRO2 in Parkinson’s Disease. Open Neurol J. 6, 1-5, 2012.
Fulltext (DOI)
Pubmed
VII. Ran C, Ramezani M, Westerlund M, Xiang F, Anvret A, Willows T, Sydow O, Johansson AC, Wirdefeldt K, Galter D and Belin AC. in Sweden. Genetic variations and mRNA expression of NRF2 in Parkinson’s disease. [Manuscript]
V. Ran C, Westerlund M, Anvret A, Willows T, Sydow O, Galter D, Belin AC. Genetic studies of the protein kinase AKT1 in Parkinson's disease. Neurosci Lett. 501, 41-44, 2011.
Fulltext (DOI)
Pubmed
VI. Ran C, Westerlund M, Olson L, Galter D, Belin AC. AKT1 Gene expression in human and rodent tissues. [Manuscript]
VII. Ran C, Ramezani M, Westerlund M, Xiang F, Anvret A, Willows T, Sydow O, Johansson AC, Wirdefeldt K, Galter D and Belin AC. in Sweden. Genetic variations and mRNA expression of NRF2 in Parkinson’s disease. [Manuscript]
VIII. Westerlund M, Ran C, Borgkvist A, Sterky FH, Lindqvist E, Lundströmer K, Pernold K, Brené S, Kallunki P, Fisone G, Olson L, Galter D. Lrrk2 and α-synuclein are co-regulated in rodent striatum. Mol Cell Neurosci. 39, 586-591, 2008.
Fulltext (DOI)
Pubmed
IX. Ran C, Westerlund M, Ramezani M, Gellhaar S, Xiang F, Fardell C, Nissbrandt H, Söderkvist P, Willows T, Johansson AC, Sydow O, Wirdefeldt K, Olson L, Galter D, Belin AC. Glucocerebrosidase (GBA) characterization in Parkinson’s disease in Sweden. [Manuscript]
X. Ran C, Willows T, Sydow O, Johansson A, Söderkvist P, Dizdar N, Ahmadi A, Olson L, Belin AC. The HLA-DRA variation rs3129882 is not associated with Parkinson's disease in Sweden. Parkinsonism Relat Disord. 19, 701-702, 2013.
Fulltext (DOI)
Pubmed
XI. Ran C, Graae L, Magnusson PKE, Pedersen NL, Olson L, Belin AC. A replication study of GWAS findings in migraine identifies association in a Swedish case-control sample. BMC Med Genet. 15:38, 2014.
Fulltext (DOI)
Pubmed
I. Anvret A, Ran C, Westerlund M, Gellhaar S, Lindqvist E, Pernold K, Lundströmer K, Duester G, Felder M.R, Galter D, Belin AC. Adh1 and Adh1/4 knockout mice as possible rodent models for presymptomatic Parkinson's disease. Behav Brain Res. 227, 252-257, 2012.
Fulltext (DOI)
Pubmed
II. Belin AC, Ran C, Anvret A, Paddock S, Westerlund M, Håkansson A, Nissbrandt H, Söderkvist P, Dizdar N, Ahmadi A, Anvret M, Willows T, Sydow O, Galter D. Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease. Neurosci Lett. 522, 30-35, 2012.
Fulltext (DOI)
Pubmed
III. Anvret A, Ran C, Westerlund M, Thelander AC, Sydow O, Lind C, Håkansson A, Nissbrandt H, Galter D, Belin AC. Possible Involvement of a Mitochondrial Translation Initiation Factor 3 Variant Causing Decreased mRNA Levels in Parkinson's disease. Parkinsons Dis. 2010, Article ID 491751, 2010.
Fulltext (DOI)
Pubmed
IV. Anvret A, Ran C, Westerlund M, Sydow O, Willows T, Olson L, Galter D, Belin AC. Genetic Screening of the Mitochondrial Rho GTPases MIRO1 and MIRO2 in Parkinson’s Disease. Open Neurol J. 6, 1-5, 2012.
Fulltext (DOI)
Pubmed
VII. Ran C, Ramezani M, Westerlund M, Xiang F, Anvret A, Willows T, Sydow O, Johansson AC, Wirdefeldt K, Galter D and Belin AC. in Sweden. Genetic variations and mRNA expression of NRF2 in Parkinson’s disease. [Manuscript]
V. Ran C, Westerlund M, Anvret A, Willows T, Sydow O, Galter D, Belin AC. Genetic studies of the protein kinase AKT1 in Parkinson's disease. Neurosci Lett. 501, 41-44, 2011.
Fulltext (DOI)
Pubmed
VI. Ran C, Westerlund M, Olson L, Galter D, Belin AC. AKT1 Gene expression in human and rodent tissues. [Manuscript]
VII. Ran C, Ramezani M, Westerlund M, Xiang F, Anvret A, Willows T, Sydow O, Johansson AC, Wirdefeldt K, Galter D and Belin AC. in Sweden. Genetic variations and mRNA expression of NRF2 in Parkinson’s disease. [Manuscript]
VIII. Westerlund M, Ran C, Borgkvist A, Sterky FH, Lindqvist E, Lundströmer K, Pernold K, Brené S, Kallunki P, Fisone G, Olson L, Galter D. Lrrk2 and α-synuclein are co-regulated in rodent striatum. Mol Cell Neurosci. 39, 586-591, 2008.
Fulltext (DOI)
Pubmed
IX. Ran C, Westerlund M, Ramezani M, Gellhaar S, Xiang F, Fardell C, Nissbrandt H, Söderkvist P, Willows T, Johansson AC, Sydow O, Wirdefeldt K, Olson L, Galter D, Belin AC. Glucocerebrosidase (GBA) characterization in Parkinson’s disease in Sweden. [Manuscript]
X. Ran C, Willows T, Sydow O, Johansson A, Söderkvist P, Dizdar N, Ahmadi A, Olson L, Belin AC. The HLA-DRA variation rs3129882 is not associated with Parkinson's disease in Sweden. Parkinsonism Relat Disord. 19, 701-702, 2013.
Fulltext (DOI)
Pubmed
XI. Ran C, Graae L, Magnusson PKE, Pedersen NL, Olson L, Belin AC. A replication study of GWAS findings in migraine identifies association in a Swedish case-control sample. BMC Med Genet. 15:38, 2014.
Fulltext (DOI)
Pubmed
Institution: Karolinska Institutet
Supervisor: Carmine Belin, Andrea
Issue date: 2014-09-11
Rights:
Publication year: 2014
ISBN: 978-91-7549-616-0
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