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Amyloidosis and Aging
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
Per Westermark, Kenneth H. Johnson
In general, most forms of amyloidosis are seen with greater frequency in humans and animals as they age.2,3 Amyloid deposits of one form or another, many of which were clinically inapparent, were reported in virtually all consecutive autopsies of individuals over 65 years of age in one study.4 This association of amyloidosis with aging appears, at least partly, to be a reflection of an increasing cumulative risk for overt or occult diseases which either directly or indirectly favor factors that lead to fibrillogenesis of the respective amyloid precursor proteins. The specific mechanisms involved in the fibrillogenesis may be different and unique for each specific form of amyloidosis.
Mechanisms of Fibril Formation and Cellular Response
Published in Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin, XIth International Symposium on Amyloidosis, 2007
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin
AL amyloidosis is the most common systemic amyloidosis in the developed world. It is a clonal plasma cell disorder, in which the immunoglobulin light chains (LC) synthesized by the plasma cells polymerize into fibrillar tissue deposits. These deposits are associated with organ dysfunction. In untreated patients, the disease progresses rapidly to organ failure and death. Research presented at the Symposium addressed the mechanisms of fibrillogenesis, tissue interaction and pathogenesis, and innovative approaches to diagnosis and treatment. In the Keynote presentation, some of these challenges were considered, and the longterm results of treatment with high-dose melphalan chemotherapy and autologous stem cell transplantation (HDM/SCT) were reviewed. Follow-up of patients treated more than 10 years ago at Boston Medical Center indicates that hematologic remissions can be maintained after such treatment, and translate into improved performance status, organ function, quality of life survival. These long-term results contrast with those for multiple myeloma, in which patients inexorably relapse after such treatment. Cautiously, we can begin to hope that long-term responders and survivors may be cured of their plasma cell disease.
Deposition and Passage of Transthyretin Through the Blood-Nerve Barrier in Recipients of Familial Amyloid Polyneuropathy Livers
Published in Gilles Grateau, Robert A. Kyle, Martha Skinner, Amyloid and Amyloidosis, 2004
M. M. Sousa, J. Ferrão, R. Fernandes, A. Guimarães, J. B. Geraldes, R. Perdigoto, L. Tomé, O. Mota, L. Negrão, A. L. Furtado, M. J. Saraiva
De novo amyloidosis occurs in the skin and nerve of recipients of FAP livers after DLT. Sites related to TTR deposition did not display signs of oxidative stress such as increase in 3-NT epitopes probably due to the reduced amount of deposited TTR. The fibrillogenesis pathway might be accelerated in adults either due to the enhancement of mechanisms involved in amyloid formation or to the downregulation of inhibitory pathways. In individuals where the liver is the sole source of mutated TTR, the protein is able to deposit in the connective tissue of the epinerve and skin, suggesting that the plasma pool of the protein is sufficient for PNS involvement in FAP. DLT using FAP livers should continue to be considered an experimental procedure under careful surveillance and recipients of FAP livers should be followed up using an extensive neurological and pathological examination.
Understanding collagen interactions and their targeted regulation by novel drugs
Published in Expert Opinion on Drug Discovery, 2021
Marialucia Gallorini, Simone Carradori
As alternative and druggable pathways and processes to be further explored we must also consider: The control of collagen arrangement is important to establish tissue-selective wound healing and limit fibrosis. Targeting collagen fibrillogenesis was also proposed to achieve therapeutic effects and block the development of fibril-rich scars in response to injury and avoid fibrotic diseases [159]. To overcome the disruption of vital functions due to excessive formation of collagen, the main players are collagen telopeptides, which promote the collagen-collagen binding and the fibril nucleation and growth through the interaction with the triple-helical telopeptide-binding region (T-TBR). Monoclonal antibodies, targeting an epitope within the C-terminal telopeptide of the α2(I) chain (anti-α2Ct), were recently proposed to reduce type I collagen fibrillogenesis in the fibrotic tissues in vivo, by direct binding to free type I procollagen and type I collagen.The upstream regulators of collagen modulate ECM rigidity versus plasticity within the fibrotic process. TGF-β, Wnt pathways, ECM components (hyaluronan, laminin, tenascin, EDA-fibronectin), and ECM receptors (mechano‐sensing integrins) establish a complex interplay of intracellular signaling networks involved in cell-matrix interactions and wound healing [88,160].
Novel challenges in the management of immunoglobulin light chain amyloidosis: from the bench to the bedside
Published in Expert Review of Hematology, 2020
Marco Basset, Mario Nuvolone, Giovanni Palladini, Giampaolo Merlini
Light chains of the λ isotype show a higher propensity to form amyloid fibrils and represent the amyloidogenic precursor in 75% of cases [5]. Major efforts have been made in studying amyloidogenic LCs in order to explain the mechanisms of fibrillation and organ tropism. Three different immunoglobulin light chain variable region (IGLV) genes code most of the amyloidogenic λ LCs: IGLV2-14, IGLV6-57, and IGLV3-1 [25–29]. An association between germline IGLV6-57, IGLV1-44, and IGKV1-33 with renal, cardiac, and hepatic involvement has been reported, respectively [29,30]. Moreover, other disease features seem also to be related to a peculiar IGLV germ-line gene usage: IGVL6-57 is associated with translocation t(11;14) and IGLV2-14 and IGKV1-33 with lower and higher serum-free light chain concentration, respectively [29]. Recently, the German and the Italian groups published the cryo-EM structures of two λ LC amyloid fibrils from the heart of two patients with AL amyloidosis [31,32]. These studies showed that misfolding and fibrils assembly depend on LC variable region sequence. Different hot spot mutations that may be involved in the first steps of aggregation have been described [33]. Particularly, mutations in the interface region of λ LC monomers within the LC dimer decrease protein stability and enhance aggregation [34]. Interestingly, different cardiotoxic light chains revealed conserved mutations. This suggests that specific highly conserved motifs may be responsible for LC fibrillogenesis and could represent possible targets for novel therapies [32].
Transthyretin Glu54Leu – an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2019
Urban Hellman, Kenneth Lång, Elisabet Ihse, Jenni Jonasson, Malin Olsson, Hans-Erik Lundgren, Björn Pilebro, Per Westermark, Jonas Wixner, Intissar Anan
It is believed that the C-terminal fragments seen in western blots for typical type A ATTR amyloid fibrils start around amino acid 50, as fragments beginning at amino acid positions 46, 49, and 52 have been reported to be present in high amounts and even being the major species in such ATTR fibrils [23–25]. Marcoux et al. have suggested that the cleavage and release of a 49–127 fragment is a result of proteolysis/fibrogensis pathway [26]. In this work, it is not known which stretches of the TTR sequence the western blot bands seen in the Glu54Leu patients correspond to, more than that they must belong to TTR50-127 since it is detected by the antibody which recognizes this part of TTR. It is possible that this new type of western blot band pattern is correlated to a third type of fibril composition, with possible differences in fibril structure as well as mechanism of fibrillogenesis. Further studies are needed to answer such questions.