The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases

Zeineddine, Rafaa; Yerbury, Justin J.

doi:10.3389/fphys.2015.00277

Cited by 49 publications

(51 citation statements)

References 72 publications

(114 reference statements)

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“…The inhibitor effect of MiT-MAB suggests a phagocytic mechanism as a secondary pathway for amyloid fibrils internalization (42). Macropinocytosis has also been associated with amyloid transcellular propagation (43). Many studies have reported a cell to cell transfer of misfolded protein and aggregates, triggering the progression of the neurodegenerative disease throughout the brain (39, 40, 44 -48).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Cell Damage in Light Chain Amyloidosis

Argany¹,

Lin²,

Misra³

et al. 2016

Journal of Biological Chemistry

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“…23 It is likely that this mode of uptake is not specific to TDP-43 but to protein aggregates in general. 24,25 Similarly, both conditioned media containing TDP-43 from cultured cells, and homogenates from ALS patient brains, have been shown to interact with cell produced TDP-43 using a split luciferase reporter 11 and transduced TDP-43 aggregates from brain material has been shown to increase cell produced TDP-43 aggregation via western blot. 8,9 It is interesting to note that the transmission rates are low in these experiments.…”

Section: Discussionmentioning

confidence: 99%

Flow cytometric measurement of the cellular propagation of TDP-43 aggregation

Zeineddine

Whiten

Farrawell

et al. 2017

Prion

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ABSTRACT. Amyotrophic lateral sclerosis is a devastating neuromuscular degenerative disease characterized by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology including TAR DNA-binding protein of 43 kDa (TDP-43) aggregates. Previous work suggests that TDP-43 can move between cells. Here we used a novel flow cytometry technique (FloIT) to analyze TDP-43 inclusions and propagation. When cells were transfected to express either mutant G294A TDP-43 fused to GFP or wild type TDP-43fused to tomato red and then co-cultured, flow cytometry detected intact cells containing both fusion proteins and using FloIT detected an increase in the numbers of inclusions in lysates from cells expressing wild type TDP-43-tomato. Furthermore, in this same model, FloIT analyses detected inclusions containing both fusion proteins. These results imply the transfer of TDP-43 fusion proteins between cells and that this process can increase aggregation of wild-type TDP-43 by a mechanism involving co-aggregation with G294A TDP-43.

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“…Macropinocytosis is now thought to be an important route for spread of prions and prion-like proteins (Zeineddine and Yerbury, 2015). Misfolded forms of the Cu-Zn superoxide dismutase protein SOD1 are linked to the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), both in familial forms of the disease in which SOD1 mutations are frequent, and in sporadic ALS.…”

Section: Contributions Of Macropinocytosis To Transmission Of Prionlimentioning

confidence: 99%

Uses and abuses of macropinocytosis

Bloomfield

Kay

2016

Journal of Cell Science

151

171

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Macropinocytosis is a means by which eukaryotic cells ingest extracellular liquid and dissolved molecules. It is widely conserved amongst cells that can take on amoeboid form and, therefore, appears to be an ancient feature that can be traced back to an early stage of evolution. Recent advances have highlighted how this endocytic process can be subverted during pathology -certain cancer cells use macropinocytosis to feed on extracellular protein, and many viruses and bacteria use it to enter host cells. Prion and prion-like proteins can also spread and propagate from cell to cell through macropinocytosis. Progress is being made towards using macropinocytosis therapeutically, either to deliver drugs to or cause cell death by inducing catastrophically rapid fluid uptake. Mechanistically, the Ras signalling pathway plays a prominent and conserved activating role in amoebae and in mammals; mutant amoebae with abnormally high Ras activity resemble tumour cells in their increased capacity for growth using nutrients ingested through macropinocytosis. This Commentary takes a functional and evolutionary perspective to highlight progress in understanding and use of macropinocytosis, which is an ancient feeding process used by single-celled phagotrophs that has now been put to varied uses by metazoan cells and is abused in disease states, including infection and cancer.

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The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases

Cited by 49 publications

References 72 publications

Cell Damage in Light Chain Amyloidosis

Cell Damage in Light Chain Amyloidosis

Flow cytometric measurement of the cellular propagation of TDP-43 aggregation

Uses and abuses of macropinocytosis

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