| 1. |
- Almandoz-Gil, Leire, et al.
(författare)
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Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways
- 2017
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Ingår i: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 110, s. 421-431
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96 h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.
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| 2. |
- Anan, Intissar, et al.
(författare)
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Amyloid fibril composition type is consistent over time in patients with Val30Met (p. Val50Met) transthyretin amyloidosis
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 17:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses.Material and methods: Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot.Results: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies.Discussion: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.
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| 3. |
- Ekmark-Lewén, Sara, et al.
(författare)
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Early fine motor impairment and behavioral dysfunction in (Thy-1)-h[A30P] alpha-synuclein mice
- 2018
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Ingår i: Brain and Behavior. - : WILEY. - 2162-3279 .- 2162-3279. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Intraneuronal inclusions of alpha-synuclein are commonly found in the brain of patients with Parkinson's disease and other a-synucleinopathies. The correlation between alpha-synuclein pathology and symptoms has been studied in various animal models. In (Thy-1)-h[A30P] alpha-synuclein transgenic mice, behavioral and motor abnormalities were reported from 12 and 15 months, respectively. The aim of this study was to investigate whether these mice also display symptoms at earlier time points.Methods: We analyzed gait deficits, locomotion, and behavioral profiles in (Thy-1)-h[A30P] alpha-synuclein and control mice at 2, 8, and 11 months of age. In addition, inflammatory markers, levels of alpha-synuclein oligomers, and tyrosine hydroxylase reactivity were studied.Results: Already at 2 months of age, transgenic mice displayed fine motor impairments in the challenging beam test that progressively increased up to 11 months of age. At 8 months, transgenic mice showed a decreased general activity with increased risk-taking behavior in the multivariate concentric square field test. Neuropathological analyses of 8- and 11-month-old mice revealed accumulation of oligomeric alpha-synuclein in neuronal cell bodies. In addition, a decreased presence of tyrosine hydroxylase suggests a dysregulation of the dopaminergic system in the transgenic mice, which in turn may explain some of the motor impairments observed in this mouse model.Conclusions: Taken together, our results show that the (Thy-1)-h[A30P] alpha-synuclein transgenic mouse model displays early Parkinson's disease-related symptoms with a concomitant downregulation of the dopaminergic system. Thus, this should be an -appropriate model to study early phenotypes of alpha-synucleinopathies.
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| 4. |
- Fagerqvist, Therese, et al.
(författare)
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Off-pathway alpha-synuclein oligomers seem to alter alpha-synuclein turnover in a cell model but lack seeding capability in vivo
- 2013
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Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 20:4, s. 233-244
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated α-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson’s disease and dementia with Lewy bodies. Experimental evidence indicates that α-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of α-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when α-synuclein oligomers were added to monomeric α-synuclein. In contrast, exogenously added α-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing α-synuclein that were treated with the oligomers displayed reduced α-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected α-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of α-synuclein oligomers into the neocortex of α-synuclein transgenic mice did not induce formation of Proteinase K resistant α-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced α-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.
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| 5. |
- Fagerqvist, Therese, et al.
(författare)
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Off-pathway α-synuclein oligomers seem to alter α-synuclein turnover in a cell model but lack seeding capability in vivo
- 2013
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Ingår i: Amyloid. - : Informa Healthcare. - 1350-6129 .- 1744-2818. ; 20:4, s. 233-244
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated alpha-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson's disease and dementia with Lewy bodies. Experimental evidence indicates that alpha-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of alpha-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when alpha-synuclein oligomers were added to monomeric alpha-synuclein. In contrast, exogenously added alpha-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing alpha-synuclein that were treated with the oligomers displayed reduced alpha-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected alpha-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of alpha-synuclein oligomers into the neocortex of alpha-synuclein transgenic mice did not induce formation of proteinase K resistant alpha-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced alpha-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.
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| 6. |
- Gustafsson, Sandra, et al.
(författare)
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Amyloid Fibril Composition as a Predictor of Development of Cardiomyopathy After Liver Transplantation for Hereditary Transthyretin Amyloidosis
- 2012
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:10, s. 1017-1023
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Tidskriftsartikel (refereegranskat)abstract
- Background. Liver transplantation (LTx) is an accepted treatment for hereditary transthyretin (TTR) amyloidosis (ATTR). However, unforeseen heart complications, especially a rapid development of cardiomyopathy after LTx has affected mortality and morbidity. Recently, a relationship between ATTR-fibril composition and cardiomyopathy has been noted. The aim of this study was to investigate whether development of cardiomyopathy and heart failure in LTx ATTR amyloid patients is related to amyloid fibril composition.Methods. Twenty-four patients with hereditary ATTR amyloidosis who had undergone LTx and have had their amyloid fibril type tested were available for the study. They had been examined by echocardiography including tissue Doppler and speckle tracking echocardiography before and after LTx. Patients were divided into two groups according to fibril composition, 10 patients with type A fibrils (a mixture of truncated and full-length TTR) and 14 patients with type B fibrils (full-length TTR fibrils only). There was no difference in time to the follow-up echocardiography between the two groups.Results. After LTx, the group consisting of type A patients developed symptoms of heart failure and with reduced systolic and diastolic ventricular function as shown by echocardiography, whereas no similar deterioration was noted for the group of patients with type B fibrils.Conclusion. Patients with type A fibrils deteriorate an already existing cardiomyopathy and heart failure after LTx, in contrast to patients with type B fibrils. These results might have significant clinical implications in optimizing best patients selection criteria for LTx.
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| 7. |
- Hellman, Urban, 1966-, et al.
(författare)
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Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type
- 2019
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Taylor & Francis. - 0036-5513 .- 1502-7686. ; 79:6, s. 372-376
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Tidskriftsartikel (refereegranskat)abstract
- For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.
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| 8. |
- Ihse, Elisabet, et al.
(författare)
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Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis
- 2013
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Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 20:3, s. 142-150
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Tidskriftsartikel (refereegranskat)abstract
- The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients' age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients.
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| 9. |
- Ihse, Elisabet, 1977-, et al.
(författare)
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Amyloid fibrils with fragmented ATTR may be the rule in non-Val30Met ATTR amyloidosis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one composed of only intact ATTR (type B). Patients with type A fibrils have a late age of onset and signs of cardiomyopathy, while patients with type B fibrils have an early onset and much less myocardial involvement. The present study aimed to determine if the correlation between fibril type and clinical phenotype is true for familial amyloidosis in general. Cardiac and/or adipose tissue from 48 patients carrying 21 different non-TTRV30M mutations were examined, as well as 7 non-Swedish ATTRV30M patients. Fibril type was determined with western blotting and compared to the patients´ age of onset and degree of cardiomyopathy. Non-Swedish V30M patients showed the same correlation as described for Swedish V30M patients, with fibrils of only full-length ATTR (type B) linked to less myocardial involvement. In contrast, all patients with non-V30M mutations had a fibril composition with ATTR fragments (type A). Some of these patients had onset of disease at young age. The vast majority had increased thickness of left cardiac ventricle, but a few individuals had values within normal limits. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis. It also suggests that fibrils composed of only full-length ATTR is an exception, perhaps only found among young ATTRV30M amyloidosis patients.
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| 10. |
- Ihse, Elisabet, et al.
(författare)
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Proportion between wild-type and mutant protein in truncated compared to full-length ATTR : an analysis on transplanted transthyretin T60A amyloidosis patients
- 2009
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 379:4, s. 846-850
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Tidskriftsartikel (refereegranskat)abstract
- Familial ATTR amyloidosis is caused by point mutations in the transthyretin gene. The clinical manifestations are highly varied but polyneuropathy and/or cardiomyopathy are generally the main symptoms. The amyloid fibrils can either be composed of only intact ATTR molecules or intact together with fragmented ATTR species. As plasma TTR is almost exclusively synthesized in the liver, liver transplantation is performed in order to eliminate the mutant plasma TTR. The procedure has shown best results among patients with the V30M mutation, while a rapid continued cardiac deposition of wild-type (wt) TTR has been seen for many other mutations. In this paper we investigated the proportion of wtATTR in two TTRT60A patients that underwent liver transplantation; one patient died 3 weeks after surgery, the other patient survived for 12 months. As the role of fragmented TTR species in the pathogenesis is far from understood, we investigated the proportion of wt in these species separately to the full-length molecules, which has not been done before in transplanted patients. The results show a higher proportion of wtTTR in the 12-months-surviving patient than the 3-weeks-surviving patient, but interestingly this difference in wt proportion is mainly seen among the full-length, and not the fragmented, molecules.
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