| 1. |
- Gellhaar, Sandra
(författare)
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Neurodegenerative diseases studied in human brain and rodent models
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s and Alzheimer’s disease are the two most common neurodegenerative diseases world-wide, but are still little understood. Papers in this thesis examine some of the possible pathogenic mechanisms with the help of mouse models and analysis of human post-mortem tissue. Gene-based animal models have been developed to study pathological pathways during disease progression. Using mouse models with overexpression or ablation of disease-related genes we analyzed effects of pathogenic mutations on the function of the proteins. A prominent feature of patients carrying the G2019S mutation in leucine rich repeat kinase 2 (LRRK2) is a high load of Lewy Bodies, an intracellular protein accumulation highly enriched in α-synuclein. We investigated the interaction of LRRK2 and α-synuclein in transgenic mice and did not find an influence of LRRK2 expression on fibrillization of α-synuclein or dopamine neurons pathology, indicating separate pathways for the two genes causing PD. Using another genetic model with a conditional knockout of the mitochondrial transcription factor A in dopamine neurons, the MitoPark mouse, we detected reduced dopamine release and pacemaker activity in the substantia nigra several weeks before these mice develop motor dysfunction. The mRNA levels of the hyperpolarization-activated cyclic nucleotide gated channels 1-4 (HCN1-4), responsible for the pacemaking activity, were not altered in MitoPark mice, indicating that post-translational modifications occur early in the presymptomatic stages of Parkinson’s disease. To evaluate behavioral and cellular changes related to L-DOPA therapy we used older MitoPark mice, which model late stages of Parkinson’s disease. Chronic L-DOPA treatment normalized gait parameters but induced also progressing dyskinetic behavior in MitoPark mice. The treatment also caused a robust increase of TH mRNA expression in the striatum, as evidenced by RNA-Sequencing. The induction of TH in striatal neurons with an interneuronal phenotype was dependent on the degree of dopamine depletion and the L-DOPA dose. In disease-affected brain areas of patients with Parkinson’s or Alzheimer’s disease we found a significant increase in small-sized cells expressing the lysosomal enzyme myeloperoxidase. This finding supports involvement of a neuroinflammatory component in these diseases and encourages the research for anti-inflammatory treatments. Another protein implicated in the pathogenesis of neurodegeneration is the serine peptidase HTRA2. We detected altered enzyme activity and expression of HTRA2 in frontal cortex samples from Alzheimer’s disease patients. The association of a mutation in a HTRA2 allele with Alzheimer’s disease in our case-control material further supported a role of mitochondrial dysfunction in the pathology. Taken together, the studies presented in this thesis uncover changes in gene and protein expression in mouse and human samples, as well as behavioral changes in animal models of disease and will aid the development of better treatment options by increasing our knowledge of underlying pathological mechanisms.
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| 2. |
- Hedskog, Louise, et al.
(författare)
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Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models
- 2013
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:19, s. 7916-7921
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Tidskriftsartikel (refereegranskat)abstract
- It is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer's disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation. The effect of AD pathogenesis on the ER-mitochondria interplay in the brain has so far remained unknown. Here, we studied ER-mitochondria contacts in human AD brain and related AD mouse and neuronal cell models. We found uniform distribution of MAM in neurons. Phosphofurin acidic cluster sorting protein-2 and sigma 1 receptor, two MAM-associated proteins, were shown to be essential for neuronal survival, because siRNA knockdown resulted in degeneration. Up-regulated MAM-associated proteins were found in the AD brain and amyloid precursor protein (APP)(Swe/Lon) mouse model, in which up-regulation was observed before the appearance of plaques. By studying an ER-mitochondria bridging complex, inositol-1,4,5-triphosphate receptor-voltage-dependent anion channel, we revealed that nanomolar concentrations of amyloid beta-peptide increased inositol-1,4,5-triphosphate receptor and voltage-dependent anion channel protein expression and elevated the number of ER-mitochondria contact points and mitochondrial calcium concentrations. Our data suggest an important role of ER-mitochondria contacts and cross-talk in AD pathology.
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| 3. |
- 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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| 4. |
- 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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