| 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. |
- Westerlund, Marie, et al.
(författare)
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Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease.
- 2011
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Ingår i: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 25:4, s. 1345-52
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Tidskriftsartikel (refereegranskat)abstract
- The serine-protease OMI/HTRA2, required for several cellular processes, including mitochondrial function, autophagy, chaperone activity, and apoptosis, has been implicated in the pathogenesis of both Alzheimer's disease (AD) and Parkinson's disease (PD). Western blot quantification of OMI/HTRA2 in frontal cortex of patients with AD (n=10) and control subjects (n=10) in two separate materials indicated reduced processed (active, 35 kDa) OMI/HTRA2 levels, whereas unprocessed (50 kDa) enzyme levels were not significantly different between the groups. Interestingly, the specific protease activity of OMI/HTRA2 was found to be significantly increased in patients with AD (n=10) compared to matched control subjects (n=10) in frontal cortex in two separate materials. Comparison of OMI/HTRA2 mRNA levels in frontal cortex and hippocampus, two brain areas particularly affected by AD, indicated similar levels in patients with AD (n=10) and matched control subjects (n=10). In addition, we analyzed the occurrence of the OMI/HTRA2 variants A141S and G399S in Swedish case-control materials for AD and PD and found a weak association of A141S with AD, but not with PD. In conclusion, our genetic, histological, and biochemical findings give further support to an involvement of OMI/HTRA2 in the pathology of AD; however, further studies are needed to clarify the role of this gene in neurodegeneration.
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| 3. |
- Anvret, Anna
(författare)
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Genes involved in Parkinson's disease : focus on mitochondrial and detoxifying enzymes
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson's disease is a common progressive neurodegenerative disorder which mostly affects the elderly population, with a prevalence of more than 1.5% in the population over the age of 65 years. Clinical motor symptoms are mainly caused by degeneration of dopamine neurons in substantia nigra pars compacta. In order to identify genes with potential roles in the pathology of Parkinson’s disease, the candidate gene approach has been applied. Investigated genes assumed to play a role in mitochondrial maintenance were DJ-1, PTEN-induced putative kinase 1 (PINK1), the serine-protease OMI/HTRA2, mitochondrial translation initiation factor 3 (MTIF3), DNA polymerase gamma 1 (POLG1), mitochondrial Ras homolog gene family, member T1 and T2 (MIRO1, MIRO2). Genes involved in detoxification including paraoxonases (PON1, PON2, PON3) and alcohol dehydrogenases (ADH1C, ADH4) were also studied. Association studies were performed in a Swedish case-control material consisting of 619 Parkinson patients and 1564 neurologically healthy controls. The screening resulted in identification of several potential risk or protective factors such as DJ-1 Ala167Ala (c.501A>G), MTIF3 rs7669 (C>T), POLG1 CAG repeat variability and PON1 rs854571 (G>A). MIRO1 and MIRO2 need further investigations before they can be excluded as contributing factors. The investigation of OMI/HTRA2 A141S (G>T) in Parkinson and Alzheimer patients resulted in an association with Alzheimer’s disease. In situ hybridization of human postmortem brain tissue was used to detect any alteration of PINK1 mRNA expression in Parkinson patients and of OMI/HTRA2 mRNA in patients with either Parkinson’s or Alzhemier’s disease. No differences compared to control levels were observed for the two genes. Protein quantification of OMI/HTRA2 in frontal cortex indicated reduced levels of the active enzyme form and increased protease activity in patients with Alzheimer’s disease. Using quantitative real-time PCR we detected a reduction of mRNA expression from the MTIF3 rs7669 minor allele. Based on previous report on association of genetic variants in ADH1C and ADH4 with Parkinson’s disease, we studied spontaneous and drug induced locomotor behavior in Adh1 and Adh4 knockout mice, and in Adh1/4 double knockout mice with respect to dopamine-system-related activity and olfactory function. Neurotransmitter levels were analyzed with high-performance liquid chromatography in different brain regions. All three knockout strains displayed increased drug induced behavior, as well as alteration of levels of monoamines and their metabolites compared to wild-type littermates. Adh4-/- mice had a reduced sense of smell as well as reduction of dopamine in the olfactory bulb, and results from Adh1/4-/- pointed in the same direction. In conclusion, the findings presented in this thesis suggest genetic variability has an important role in the pathogenesis of Parkinson’s disease. The disease is a multifactorial and genetically complex disorder for which the etiology is unknown in most of the cases. It needs to be resolved how different molecular pathways involving different genes individually or together, contribute to disease by causing degeneration of dopamine neurons and other neuron types.
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