The AL Amyloid Fibril: Looking for a Link between Fibril Formation and Structure
06 Aug 2021-Vol. 2, Iss: 3, pp 505-514
TL;DR: Recent biochemical and biophysical studies that have expanded knowledge on how versatile the structure of AL fibrils in patients is are reviewed and highlighted their implications for the molecular mechanism of fibril formation in AL amyloidosis are highlighted.
Abstract: The formation and deposition of fibrils derived from immunglobulin light chains is a hallmark of systemic AL amyloidosis. A particularly remarkable feature of the disease is the diversity and complexity in pathophysiology and clinical manifestations. This is related to the variability of immunoglobulins, as virtually every patient has a variety of mutations resulting in their own unique AL protein and thus a unique fibril deposited in the body. Here, I review recent biochemical and biophysical studies that have expanded our knowledge on how versatile the structure of AL fibrils in patients is and highlight their implications for the molecular mechanism of fibril formation in AL amyloidosis.
Citations
More filters
••
TL;DR: In this article, high-resolution structures of amyloid fibrils formed from normally-folded proteins have revealed non-native conformations of the polypeptide chains, in contrast to earlier models that posited a role for assembly of partially folded proteins.
28 citations
••
TL;DR: In this paper , the first case of concurrent AL amyloidosis and a subclass of MGRS, light chain proximal tubulopathy (LCPT), was reported in a 53-year-old female with smoldering myeloma immunoglobulin G kappa.
Abstract: Due to differences in the protein folding mechanisms, it is exceedingly rare for amyloid light chain (AL) amyloidosis and monoclonal gammopathy of renal significance (MGRS) to coexist. We herein report the first case of concurrent AL amyloidosis and a subclass of MGRS, light chain proximal tubulopathy (LCPT). The 53‐year‐old female was diagnosed with smoldering myeloma immunoglobulin G kappa and AL amyloidosis with deposits in fat and gastrointestinal tissue. The kidney biopsy did not show amyloid deposits but electron microscopy revealed the presence of LCPT with crystal formation in proximal tubular epithelial cells. This case illustrates the complex pathophysiology of protein deposition in monoclonal gammopathies.
References
More filters
••
TL;DR: A large number of patients with atypical central giant cell granuloma are receiving treatment with a cocktail of chemotherapy and/or radiation, and the prognosis is improving.
Abstract: SINCE Cohen's review of amyloidosis was published in the Journal in 1967, there have been major advances in our understanding of what was less than a decade ago an untreatable, usually lethal disease complex of unknown nature, cause, and pathogenesis. Much of the mystery about the character of the "waxy, eosinophilic" tissue deposits, which Virchow believed in 1853 to be of polysaccharide composition and consequently designated as "amyloid" (starch-like or cellulose-like) has now yielded to investigations employing a wide variety of chemical and physical techniques. Once it was demonstrated that unique fibrillar components comprised over 90 per cent of amyloid . . .
1,714 citations
••
TL;DR: Cryo-electron microscopy reveals the structures of α-synuclein filaments from the brains of individuals with multiple system atrophy, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain.
Abstract: Synucleinopathies, which include multiple system atrophy (MSA), Parkinson’s disease, Parkinson’s disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases1. Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of α-synuclein in brain cells2,3. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous molecules are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that α-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies4–9, the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, especially because of the unmet clinical need to be able to image filamentous α-synuclein inclusions in the human brain. Cryo-electron microscopy reveals the structures of α-synuclein filaments from the brains of individuals with multiple system atrophy.
373 citations
••
TL;DR: This work reviews and attempts to reconcile the numerous and sometimes conflicting studies on the targeting of SHM to immunoglobulin loci, and highlights areas that hold promise for further investigation.
Abstract: Somatic hypermutation (SHM) introduces mutations in the variable region of immunoglobulin genes at a rate of approximately 10(-3) mutations per base pair per cell division, which is 10(6)-fold higher than the spontaneous mutation rate in somatic cells. To ensure genomic integrity, SHM needs to be targeted specifically to immunoglobulin genes. The rare mistargeting of SHM can result in mutations and translocations in oncogenes, and is thought to contribute to the development of B-cell malignancies. Despite years of intensive investigation, the mechanism of SHM targeting is still unclear. We review and attempt to reconcile the numerous and sometimes conflicting studies on the targeting of SHM to immunoglobulin loci, and highlight areas that hold promise for further investigation.
355 citations
••
TL;DR: Cryo-EM is used to structurally characterise brain derived Aβ amyloid fibrils and it is found that they are polymorphic and right-hand twisted, which differs from in vitro generated Aβ fibril.
Abstract: The formation of Aβ amyloid fibrils is a neuropathological hallmark of Alzheimer's disease and cerebral amyloid angiopathy. However, the structure of Aβ amyloid fibrils from brain tissue is poorly understood. Here we report the purification of Aβ amyloid fibrils from meningeal Alzheimer's brain tissue and their structural analysis with cryo-electron microscopy. We show that these fibrils are polymorphic but consist of similarly structured protofilaments. Brain derived Aβ amyloid fibrils are right-hand twisted and their peptide fold differs sharply from previously analyzed Aβ fibrils that were formed in vitro. These data underscore the importance to use patient-derived amyloid fibrils when investigating the structural basis of the disease.
347 citations
••
TL;DR: The results are consistent with a mechanism for the disease process in which the VL domain, either before or after proteolytic cleavage from the L-chain constant region domain, unfolds by virtue of one or more destabilizing amino acid replacements to generate an aggregation-prone nonnative state.
Abstract: Light-chain (L-chain) amyloidosis is characterized by deposition of fibrillar aggregates composed of the N-terminal L-chain variable region (VL) domain of an immunoglobulin, generally in individuals overproducing a monoclonal L chain. In addition to proteolytic fragmentation and high protein concentration, particular amino acid substitutions may also contribute to the tendency of an L chain to aggregate in L-chain amyloidosis, although evidence in support of this has been limited and difficult to interpret. In this paper we identify particular amino acid replacements at specific positions in the VL domain that are occupied at frequencies significantly higher in those L chains associated with amyloidosis. Analysis of the structural model for the VL domain of the Bence-Jones protein REI suggests that these positions play important roles in maintaining domain structure and stability. Using an Escherichia coli expression system, we prepared single-point mutants of REI VL incorporating amyloid-associated amino acid replacements that are both rare and located at structurally important positions. These mutants support ordered aggregate formation in an in vitro L-chain fibril formation model in which wild-type REI VL remains soluble. Moreover, the ability of these sequences to aggregate in vitro correlates well with the extent to which domain stability is decreased in denaturant-induced unfolding. The results are consistent with a mechanism for the disease process in which the VL domain, either before or after proteolytic cleavage from the L-chain constant region domain, unfolds by virtue of one or more destabilizing amino acid replacements to generate an aggregation-prone nonnative state.
323 citations