Cross-Seeding of Misfolded Proteins: Implications for Etiology and Pathogenesis of Protein Misfolding Diseases

Morales, Rodrigo; Moreno-González, Inés; Soto, Claudio

doi:10.1371/journal.ppat.1003537

Cited by 187 publications

(178 citation statements)

References 40 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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“…Although most studies of amyloid formation have focused on individual disease-specific peptides, interactions of peptides associated with different amyloid diseases may modulate amyloid formation pathways and pathogenicity (38). IAPP and amyloid-β share 50% sequence similarity and were found to cross-react both in vitro (40) and in vivo (41).…”

Section: Discussionmentioning

confidence: 99%

“…In support, reports have suggested that patients with T2D are predisposed toward PD (36,37). For Alzheimer's disease (AD), a direct link with T2D was found (15,38). Amyloid fiber seeds of the AD peptide, amyloid-β, were shown to efficiently accelerate amyloid formation of IAPP in vitro (39,40) and IAPP was part of amyloid-β plaque found in mice brains (41).…”

mentioning

confidence: 86%

Cross-talk between amyloidogenic proteins in type-2 diabetes and Parkinson’s disease

Horváth

Wittung-Stafshede

2016

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

140

125

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In type-2 diabetes (T2D) and Parkinson's disease (PD), polypeptide assembly into amyloid fibers plays central roles: in PD, α-synuclein (aS) forms amyloids and in T2D, amylin [islet amyloid polypeptide (IAPP)] forms amyloids. Using a combination of biophysical methods in vitro we have investigated whether aS, IAPP, and unprocessed IAPP, pro-IAPP, polypeptides can cross-react. Whereas IAPP forms amyloids within minutes, aS takes many hours to assemble into amyloids and pro-IAPP aggregates even slower under the same conditions. We discovered that preformed amyloids of pro-IAPP inhibit, whereas IAPP amyloids promote, aS amyloid formation. Amyloids of aS promote pro-IAPP amyloid formation, whereas they inhibit IAPP amyloid formation. In contrast, mixing of IAPP and aS monomers results in coaggregation that is faster than either protein alone; moreover, pro-IAPP can incorporate aS monomers into its amyloid fibers. From this intricate network of cross-reactivity, it is clear that the presence of IAPP can accelerate aS amyloid formation. This observation may explain why T2D patients are susceptible to developing PD.α-synuclein | fluorescence | amyloid | atomic force microscopy | amylin

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“…Evidence is not lacking for candidate mechanisms of the latter sort -in addition to disruption of proteostasis, it is possible, for example, that PrP Sc impairs extracellular clearance of amyloid-β or that direct molecular cross-templating occurs. 10 Any such alternative hypothesis, however, must be consistent with the unexpectedly intense amyloid-β pathology found in four of the patients with iatrogenic CJD, as well as the age-specific distribution of amyloid-β pathology in all patients with CJD. Further research is needed to address these questions.…”

mentioning

confidence: 86%