| 1. |
- Amarzguioui, Mohammed, et al.
(författare)
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Extensive Intimal Apolipoprotein A1-Derived Amyloid Deposits in a Patient with an Apolipoprotein A1 Mutation
- 1998
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 242:3, s. 534-539
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Tidskriftsartikel (refereegranskat)abstract
- In the aortic intima amyloid deposits are often associated with atherosclerotic plaques. In a recent study of one patient with aortic intimal amyloid the major fibril protein was an N-terminal fragment of apolipoprotein A1 (apoA1) consisting of 69 amino acid residues. In the present study, we have screened the apoA1 gene for mutations in autopsy cases with aortic intimal amyloid immunohistochemically positive for apoA1, using single stranded conformational polymorphism (SSCP) analysis and DNA sequencing. All cases except one had a normal apoA1 gene sequence. One case of exceptionally severe atherosclerosis combined with extensive intimal amyloid deposits showed an apoA1 deletion corresponding to Lys 107. Thus, wild type apoA1 is amyloidogenic but our findings suggest that the expression of a mutant apoA1-form may be associated with enhanced amyloidogenicity.
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| 2. |
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| 3. |
- Bergström, Joakim, et al.
(författare)
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Two different types of amyloid deposits - apolipoprotein A-IV and transthyretin - in a patient with systemic amyloidosis
- 2004
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Ingår i: Lab. Invest.. ; 84, s. 981-988
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Tidskriftsartikel (refereegranskat)abstract
- Certain forms of systemic amyloidosis have been associated with the pathologic deposition as fibrils of three different apolipoprotein-related proteins--apolipoprotein A-I, apolipoprotein A-II, and serum amyloid A. We have previously reported (Bergstrom et al, Biochem Biophys Res Commun 2001;285:903-908) that amyloid fibrils extracted from the heart of an elderly male with senile systemic amyloidosis contained, in addition to wild-type transthyretin-related molecules, an N-terminal fragment of yet a fourth apolipoprotein--apolipoprotein A-IV (apoA-IV). We now provide the results of our studies that have established the complete amino-acid sequence of this approximately 70-residue component and, additionally, have shown this protein to be the product of an unmutated apoA-IV gene. Notably, the apoA-IV and transthyretin fibrils were not codeposited but, rather, had anatomically distinct patterns of distribution within the heart and other organs, as evidenced immunohistochemically, by variation in the ultra structural morphology and by differences in the intensity of Congo red birefringence. These findings provide the first conclusive evidence that two separate forms of amyloid, each derived from a wild-type amyloidogenic precursor protein, were present in a patient with systemic amyloidosis.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Enqvist, Stina, et al.
(författare)
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Fibril protein fragmentation pattern in systemic AL-amyloidosis
- 2009
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 219:4, s. 473-480
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin light chain (AL)-amyloidosis was one of the first types of amyloidosis discovered and still little is known about its pathogenic mechanisms. One major obstacle is the very heterogeneous condition; in fact, every patient could be considered to have their own disease since symptoms and outcome vary enormously. The reason for this is not known but intrinsic factors of the immunoglobulin light chain (LC) and the fact that every LC is unique seem to be important. Post-translational modifications such as glycosylation and proteolysis are most certainly involved. By using western blotting, we studied in detail the proteolytic pattern in six patients with AL-amyloidosis of kappa type with the aid of three peptide antisera against two domains in the constant segment and one conserved domain in framework 3 of the variable region. Materials from one to five organs were analysed. The result clearly demonstrates that the fragmentation pattern was similar in amyloid of different organs in one patient but differed greatly between patients. Full-length, N-, and C-terminal fragments were detected with the three antisera. The results strongly support the hypothesis that proteolytic cleavage occurs after fibril formation.
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| 8. |
- Enqvist, Stina, et al.
(författare)
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Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis
- 2007
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 2:10, s. e981-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Amyloid is insoluble aggregated proteins deposited in the extra cellular space. About 25 different proteins are known to form amyloid in vivo and are associated with severe diseases such as Alzheimeŕs disease, prion diseases and type-2 diabetes. Light chain (AL) -amyloidosis is unique among amyloid diseases in that the fibril protein, a monoclonal immunoglobulin light chain, varies between individuals and that no two AL-proteins with identical primary structures have been described to date. The variability in tissue distribution of amyloid deposits is considerably larger in systemic AL-amyloidosis than in any other form of amyloidosis. The reason for this variation is believed to be based on the differences in properties of the amyloidogenic immunoglobulin light chain. However, there is presently no known relationship between the structure of an AL-protein and tissue distribution. METHODOLOGY/PRINCIPAL FINDINGS: We compared the pattern of amyloid deposition in four individuals with amyloid protein derived from variable light chain gene O18-O8, the source of a high proportion of amyloidogenic light chains, and in whom all or most of the fibril protein had been determined by amino acid sequencing. In spite of great similarities between the structures of the proteins, there was a pronounced variability in deposition pattern. We also compared the tissue distribution in these four individuals with that of four other patients with AL-amyloid derived from the L2-L16 gene. Although the interindividual variations were pronounced, liver and kidney involvement was much more evident in the latter four. CONCLUSIONS/SIGNIFICANCE: We conclude that although the use of a specific gene influences the tissue distribution of amyloid, each light chain exhibits one or more determinants of organ-specificity, which originate from somatic mutations and post-translational modifications. Eventual identification of such determinants could lead to improved treatment of patients with AL amyloidosis.
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| 9. |
- Larsson, Annika, et al.
(författare)
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Lactadherin binds to elastin -a starting point for medin amyloid formation?
- 2006
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Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 13:2, s. 78-85
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Tidskriftsartikel (refereegranskat)abstract
- Medin amyloid is found in the medial layer of the aorta in almost 100% of the Caucasian population over 50 years of age. The medin fragment is 5.5 kDa and derives from the C2-like domain of the precursor protein lactadherin. We have previously reported immunohistochemical findings showing that medin amyloid co-localizes with elastic fibers of arteries and herein we show that lactadherin also is associated with elastic structures of human aortic material. In addition, results from in vitro binding assays demonstrate that both medin and lactadherin bind to tropoelastin in a concentration-dependent fashion, suggesting that the lactadherin-tropoelastin interaction is mediated via the medin domain. It is possible that lactadherin, which is a cell adhesion protein, in this way connects smooth muscle cells to the elastic fibers of arteries. Given that both medin and lactadherin interact with elastic fibers, elastin is probably an important component in the formation of medin amyloid.
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| 10. |
- Larsson, Annika, et al.
(författare)
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Unwinding fibril formation of medin, the peptide of the most common form of human amyloid.
- 2007
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 361:4, s. 822-828
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Tidskriftsartikel (refereegranskat)abstract
- Medin amyloid affects the medial layer of the thoracic aorta of most people above 50 years of age. The consequences of this amyloid are not completely known but the deposits may contribute to diseases such as thoracic aortic aneurysm and dissection or to the general diminished elasticity of blood vessels seen in elderly people. We show that the 50-amino acid residue peptide medin forms amyloid-like fibrils in vitro. With the use of Congo red staining, Thioflavin T fluorescence, electron microscopy, and a solid-phase binding assay on different synthetic peptides, we identified the last 18-19 amino acid residues to constitute the amyloid-promoting region of medin. We also demonstrate that the two C-terminal phenylalanines, previously suggested to be of importance for amyloid formation, are not required for medin amyloid formation.
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| 11. |
- Mucchiano, Gerd, et al.
(författare)
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Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta
- 2001
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Ingår i: Journal of Pathology. - 0022-3417 .- 1096-9896. ; 193:2, s. 270-275
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that the amyloid localized to the aortic intima may be a biochemical entity different from other forms of localized amyloid. The amyloid fibril protein in one patient studied consisted of an N-terminal fragment of apolipoprotein A-1 (apo A-1). Since this patient was later shown to carry a missense mutation in the apo A-1 gene, leading to a deletion at position 107 of the mature protein, the question remained whether wild-type apo A-1 is amyloidogenic. In autopsy specimens from the thoracic aorta from 69 individuals, intimal atherosclerotic plaque-related amyloid was present in 11 cases (16%) and amyloid outside plaques in 37 cases (54%). The immunoreactivity of amyloid localized to the aortic intima was evaluated with the aid of antisera against N-terminal segments of apo A-1. The amyloid in association with atherosclerotic plaques was positively labelled by immunohistochemistry. The amyloid fibril protein from one patient, previously shown not to carry any mutation in the apo A-1 gene, was purified and shown by amino acid sequence analysis to be of apo A-1 nature. The result shows that wild-type apo A-1 is amyloidogenic and gives rise to a common localized form of amyloid associated with atherosclerosis.
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| 12. |
- Thompson, Keith M, et al.
(författare)
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Articular, monoclonal gamma3 heavy-chain deposition disease: characterization of a partially deleted heavy-chain gene and its protein product synthesized in vivo and in vitro.
- 2003
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 48:11, s. 3266-3271
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Tidskriftsartikel (refereegranskat)abstract
- Objective A patient presented with heavy-chain deposition disease (HCDD), exhibiting severe erosive polyarthropathy caused by synovial deposits of abnormal monoclonal, heavily deleted free 3 heavy chains lacking the VH and CH1 domains. The absence of VH was surprising, since it is considered important for pathogenic tissue deposition. This study was undertaken to analyze the genetic structure of the heavy chain, the protein product synthesized in vitro, and that deposited in the synovium in comparison with the serum and urinary proteins. Methods Hybridomas were made by fusion of blood and bone marrow mononuclear cells with mouse myeloma cells. Cloned B cell hybridomas secreting 3 were selected and analyzed by polymerase chain reaction. Purified hybridoma Ig was sequenced by Edman degradation. Antiserum raised to a peptide corresponding to residues 2-15 of the truncated VH was used in Western blots of synovial tissue. Results The hybridomas secreted free 3 chains consisting of a VH4 gene truncated 21 nucleotides into the first complementarity-determining region and then reading straight into the hinge region. The amino acid sequence confirmed the presence of residues 1-32 of the VH4 gene. Immunoblotting of synovial tissue showed the presence of Ig with truncated VH. Conclusion The 3 heavy chain had a deletion of VH from codon 33 and of the entire CH1. In vivo, the 32 VH amino acids were proteolytically degraded. In the joint, however, the 32 residues of VH remained intact, consistent with a pathogenic role of VH for tissue deposition. To our knowledge, this is the first reported case of HCDD causing an erosive, polyarticular arthropathy as the dominating clinical feature.
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| 13. |
- Westermark, Gunilla T., et al.
(författare)
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AA-amyloidosis. Tissue component-specific association of various protein AA subspecies and evidence of a fourth SAA gene product
- 1990
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Ingår i: American Journal of Pathology. - 0002-9440. ; 137:2, s. 377-383
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Tidskriftsartikel (refereegranskat)abstract
- Protein AA, the major repetitive protein subunit present in fibrils deposited in AA-amyloidosis, is an N-terminal cleavage product of a 104-amino acid precursor, serum amyloid A (SAA). Protein AA subspecies varying between 45 and 94 amino acids in length have been described. In this study it is shown that the different protein AA subspecies are not evenly distributed in amyloid deposits and that in single patients, certain subspecies of protein AA are deposited in specific tissue component sites. Thus larger protein AA subspecies occur in lower concentration in amyloid in the glomeruli compared to other sites and are especially found in amyloid in vessel walls. Three different SAA forms have been predicted from genomic and complementary DNA studies. The existence of a fourth type has been suspected from amino acid sequence studies of purified SAA. Protein AA derived from this fourth type of SAA is now shown to be present in amyloid fibrils in one of the patients studied in this paper.
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| 14. |
- Westermark, Per, et al.
(författare)
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Apolipoprotein A1-derived amyloid in human aortic atherosclerotic plaques
- 1995
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Ingår i: American Journal of Pathology. - 0002-9440 .- 1525-2191. ; 147:5, s. 1186-1192
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid deposits in the aortic intima are very common in association with atherosclerosis and aging. In the present study, a major fibril protein purified from amyloid present in human atherosclerotic plaques was shown to be a 69-amino acid N-terminal fragment of apolipoprotein AI. Although senile form of localized apolipoprotein AI-derived amyloidosis has recently been documented in pulmonary vessels of dogs, this is the first example of a localized human amyloid derived from this apolipoprotein.
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