| 1. |
- Anvret, Anna, et al.
(författare)
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DJ-1 Mutations are Rare in a Swedish Parkinson Cohort.
- 2011
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Ingår i: The open neurology journal. - 1874-205X. ; 5, s. 8-11
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the PARK7 gene, DJ-1, have been reported to cause early-onset and familial Parkinson's disease (PD). The function of DJ-1 and how it contributes to the development of the disease is not clear today, but several studies report that DJ-1 is responsive to oxidative stress and important for the maintenance of mitochondria. We have screened three coding regions of DJ-1 (exon 2, 5 and 7) in a Swedish Parkinson cohort. The Swedish PD material consisted of 67 patients with a self reported positive family history of PD and 77 patients with early-onset of disease (≤50 years old). We detected two patients with the previously reported synonymous mutation, Ala167Ala (c.501A>G, rs71653621), in exon 7. No Ala167Ala carriers were identified among 213 neurologically healthy Swedish controls. Mechanisms by which the synonymous Ala167Ala mutation can have consequences are unknown. It may affect the mRNA stability, secondary structure of mRNA, synthesis, turnover, protein folding and function. We could show a 1.3% decrease in DJ-1 mRNA folding energy in the A
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| 2. |
- Anvret, Anna, et al.
(författare)
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Possible involvement of a mitochondrial translation initiation factor 3 variant causing decreased mRNA levels in Parkinson's disease.
- 2010
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Ingår i: Parkinson's disease. - : Hindawi Limited. - 2042-0080. ; 2010
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Tidskriftsartikel (refereegranskat)abstract
- Genes important for mitochondrial function have been implicated in Parkinson's disease (PD). Mitochondrial translation initiation factor 3 (MTIF3) is a nuclear encoded protein required for the initiation of complex formation on mitochondrial ribosomes. Dysfunction of MTIF3 may impair mitochondrial function and dopamine neurons appear to be particularly vulnerable to oxidative stress, which may relate to their degeneration in PD. An association was recently reported between the synonymous rs7669(C>T) in MTIF3 and PD in a German case-control material. We investigated rs7669 in a Swedish Parkinson case-control material. The study revealed no significant association of the individual genotypes or alleles with PD. When comparing the combined TT/CT-genotypes versus the CC-genotype, we observed a significant association (P = .0473) with PD. We also demonstrated that the TT-genotype causes a significant decrease in MTIF3 mRNA expression compared to the CC-genotype (P = .0163). Our findings support the hypothesis that MTIF3 may be involved in the etiology of PD.
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| 3. |
- Belin, Andrea Carmine, et al.
(författare)
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Calcitonin gene-related peptide (CGRP) and cluster headache
- 2020
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Ingår i: Brain Sciences. - : MDPI AG. - 2076-3425. ; 10:1
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Forskningsöversikt (refereegranskat)abstract
- Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.
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| 4. |
- Edvinsson, Jacob C.A., et al.
(författare)
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MERTK in the rat trigeminal system : a potential novel target for cluster headache?
- 2024
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Ingår i: Journal of Headache and Pain. - 1129-2369 .- 1129-2377. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- The trigeminal system is key to the pathophysiology of migraine and cluster headache, two primary headache disorders that share many features. Recently, MER proto-oncogene tyrosine kinase (MERTK), a cell surface receptor, was strongly associated with cluster headache through genetic studies. Further, the MERTK ligand galectin-3 has been found to be elevated in serum of migraine patients. In this study, MERTK and MERTK ligands were investigated in key tissue to better understand their potential implication in the pathophysiology of primary headache disorders. Immunohistochemistry was used to map MERTK and galectin-3 expression in rat trigeminal ganglia. RT-qPCR was used to assess MERTK gene expression in blood, and ELISA immunoassays were used for MERTK ligand quantification in serum from study participants with and without cluster headache. MERTK gene expression was elevated in blood samples from study participants with cluster headache compared to controls. In addition, MERTK ligand galectin-3 was found at increased concentration in the serum of study participants with cluster headache, whereas the levels of MERTK ligands growth arrest specific 6 and protein S unaffected. MERTK and galectin-3 were both expressed in rat trigeminal ganglia. Galectin-3 was primarily localized in smaller neurons and to a lesser extent in C-fibres, while MERTK was found in satellite glia cells and in the outer membrane of Schwann cells. Interestingly, a strong MERTK signal was found specifically in the region proximal to the nodes of Ranvier. The overexpression of MERTK and galectin-3 in tissue from study participants with cluster headache, as well as the presence of MERTK in rat peripheral satellite glia cells and Schwann cells in the trigeminal ganglia, further highlights MERTK signalling as an interesting potential future therapeutic target in primary headache. Graphical Abstract: (Figure presented.)
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| 5. |
- Ran, Caroline, et al.
(författare)
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Glucocerebrosidase variant T369M is not a risk factor for Parkinson's disease in Sweden.
- 2022
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Ingår i: Neuroscience Letters. - : Elsevier. - 0304-3940 .- 1872-7972. ; 784
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Genetic variants in the Beta-glucocerebrosidase gene (GBA1) is a known risk factor for Parkinson's disease. The GBA1 mutations L444P, N370S and many other have been shown to associate with the disease in populations with diverse background. Some GBA1 polymorphisms have a less pronounced effect, and their pathogenicity has been debated. We have previously found associations with L444P, N370S and E326K and Parkinson's disease in Sweden.METHOD: In this study we used pyrosequencing to genotype the T369M variant in a large Swedish cohort consisting of 1,131 patients with idiopathic Parkinson's disease, and 1,594 control subjects to evaluate the possibility of this variant conferring an increased risk for Parkinson's disease.RESULTS: The minor allele frequency was 2.15% in patients and 1.76% in controls. Statistical analysis showed that there was no significant difference in allele frequency between patients and control subjects, p-value 0.37, Odds Ratio 1.23 with a 95% confidence interval of 0.82-1.83.CONCLUSION: Our results suggest that T369M is not a risk factor for Parkinson's disease in the Swedish population.
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| 6. |
- Ran, Caroline, et al.
(författare)
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No association between rs7077361 in ITGA8 and Parkinson’s disease in Sweden
- 2016
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Ingår i: Open Neurology Journal. - 1874-205X. ; 10, s. 25-29
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Tidskriftsartikel (refereegranskat)abstract
- Background: Integrin alpha 8 (ITGA8) encodes the alpha 8 subunit of the integrin alpha8beta1 protein and has recently been suggested as a new candidate gene for Parkinson’s disease, an age related neurodegenerative disease with unknown etiology. ITGA8 is a transmembrane protein involved in several cellular processes, such as cell adhesion, migration and cytoskeletal rearrangement. Objective: Screen a Swedish case control material for rs7077361, a genetic variant in ITGA8, in order to investigate its possible implication in Parkinson’s disease in Sweden. Method: Rs7077361 was genotyped using TaqMan quantitative Real-time PCR and tested for association using appropriate statistical methods. Results: We have screened 502 Swedish Parkinson patients and 599 healthy control individuals for rs7077361 in ITGA8. This genetic variant was in Hardy Weinberg equilibrium in the Swedish population. Allele and genotype frequencies were highly similar between the patients and controls and statistical testing showed that this genetic maker did not associate with Parkinson’s disease (p=0.67). Conclusion: Our results do not support the hypothesis of ITGA8 as a candidate gene for Parkinson’s disease in Sweden. © Ran et al.
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| 7. |
- Ran, Caroline
(författare)
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On genes involved in common neurological disorders : focus on Parkinson's disease
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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