Branching in Amyloid Fibril Growth

Andersen, Christian Beyschau; Yagi, Hisashi; Manno, Mauro; Martorana, Vincenzo; Ban, Takashi; Christiansen, Gunna; Otzen, Daniel E.; Goto, Yuji; Rischel, Christian

doi:10.1016/j.bpj.2008.11.024

Cited by 149 publications

(182 citation statements)

References 45 publications

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“…In vitro seeded acceleration of protein fibrillation has been reported in many proteins (62,63). We previously demonstrated that the presence of preformed aggregates in vitro accelerate the fibril formation reaction (64,65).…”

Section: Journal Of Biological Chemistry 19819mentioning

confidence: 89%

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

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Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis. Light chain (AL)2 amyloidosis is a protein misfolding disease characterized by extracellular deposition of immunoglobulin light chains (LC) as amyloid fibrils. LC proteins are comprised of two distinct domains: the variable (V L ) and constant (C L ) domains (also called LC full-length (FL) protein to differentiate with the V L domain). In patients with AL amyloidosis, the LC aggregate and deposit in vital organs, causing organ failure and death (1). The factors governing deposition in individual tissues are unknown. Patients with cardiac AL amyloidosis have the worst prognosis, with a median survival of less than a year (2, 3).The finding that the V L was the primary component of amyloid fibrils influenced previous biophysical studies (4,5). Recent proteomic studies have demonstrated that amyloid deposits are likely heterogeneous in nature and can be formed by FL, V L , C L , or mixtures of all types of LC fragments (6 -8). Thermodynamic studies proposed a stabilizing role for the 3C L domain in the stability and a modulating effect on fibril formation (9). Recently, our laboratory has demonstrated that the C L domain modulates the amyloid formation reaction but has no effect on the stability of the protein (10).Soluble monoclonal LC, isolated from patients with amyloidosis, can impair rat cardiomyocyte function (11) and induce apoptotic events in mouse cardiomyocytes (12, 13). Also, urinederived LC can be internalized into primary rat cardiac fibroblasts (14) and primary human renal mesangial cells (15) through a pinocytic pathway (16) or via receptor, clathrin-mediated mechanisms, respectively (15).Within the amyloid field, it is widely accepted that oligomeric species are potentially more toxic than mature fibrils (17-20). However, toxicity associated with amyloid fibrils may also be pathologically relevant. Engel et al. (21) described a mechanism in which growth of islet amyloid associated polypeptides fibrils is re...

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Section: Journal Of Biological Chemistry 19819mentioning

confidence: 89%

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

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“…For example, if fibrils become nucleated on the surface of a preexisting fibril (38), it is possible that the seed partially orients the daughter filament. Furthermore, total internal reflection fluorescence microscopy revealed the outgrowth of amyloidlike fibrils in vitro and the formation of fibril bundles due to fibril branching reactions (39) or the formation of star-like spherulites due to a radial extension of fibrils from a seed (40,41).…”

Section: Discussionmentioning

confidence: 99%

Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits

Kollmer

Meinhardt

Haupt

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.aggregation | conformational disease | electron tomography | protein assembly | prion

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“…Exponential increase in weight-averaged aggregate mass can be associated with either reactionlimited cluster-cluster aggregation 42,43 or secondary nucleation mechanisms. 28,44,45 Secondary nucleation mechanisms are often observed for fibril-forming proteins capable of generating new fibril ends by branching or breakage mechanisms, and reactionlimited cluster-cluster aggregation is a coagulation process where the rate of coalescence of two clusters is not dependent upon cluster size. The fundamental difference between these two mechanisms manifests itself through the conversion of monomers into aggregates: in secondary nucleation, the aggregate mass increases exponentially, while this is not explicit in coagulation.…”

Section: Coagulation Governs Aggregate Growthmentioning

confidence: 99%

Aggregation of a multidomain protein: A coagulation mechanism governs aggregation of a model IgG1 antibody under weak thermal stress

et al. 2010

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Using an IgG1 antibody as a model system, we have studied the mechanisms by which multidomain proteins aggregate at physiological pH when incubated at temperatures just below their lowest thermal transition. In this temperature interval, only minor changes to the protein conformation are observed. Light scattering consistently showed two coupled phases: an initial fast phase followed by several hours of exponential growth of the scattered intensity. This is the exact opposite of the lagtime behavior typically observed in protein fibrillation. Dynamic light scattering showed the rapid formation of an aggregate species with a hydrodynamic radius of about 25 nm, which then increased in size throughout the experiment. Theoretical analysis of our light scattering data showed that the aggregate number density goes through a maximum in time providing compelling evidence for a coagulation mechanism in which aggregates fuse together. Both the analysis as well as size-exclusion chromatography of incubated samples showed the actual increase in aggregate mass to be linear and reach saturation long before all molecules had been converted to aggregates. The CH2 domain is the only domain partly unfolded in the temperature interval studied, suggesting a pivotal role of this least stable domain in the aggregation process. Our results show that for multidomain proteins at temperatures below their thermal denaturation, transient unfolding of a single domain can prime the molecule for aggregation, and that the formation of large aggregates is driven by coagulation.

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Branching in Amyloid Fibril Growth

Cited by 149 publications

References 45 publications

Cell Damage in Light Chain Amyloidosis

Cell Damage in Light Chain Amyloidosis

Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits

Aggregation of a multidomain protein: A coagulation mechanism governs aggregation of a model IgG1 antibody under weak thermal stress

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