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- 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. |
- 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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