Intermediate Filaments Associate with Aggresome-like Structures in Proteostressed<i>C. elegans</i>Neurons and Influence Large Vesicle Extrusions as Exophers

Arnold, Meghan Lee; Cooper, Jason; Androwski, Rebecca J.; Ardeshna, Sohil; Melentijevic, Ilija; Smart, Anna Joelle; Guasp, Ryan J.; Nguyen, Ken; Bai, Ge; Hall, David H.; Grant, Barth D.; Driscoll, Monica

doi:10.1101/2022.08.03.501714

Cited by 3 publications

(14 citation statements)

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“…To this end, 14-3-3 represented the most discerning marker in huIgG4 + -EVs. This is of interest, as 14-3-3 protein was recently shown to be required for exopher-formation in C. elegans neurons 20 . In comparison to nephrotic non-MN patients, huIgG4 + -EVs isolated from MN-patient urines contained abundant podocyte proteins such as THSD7A, PLA2R1, Nephrin, Podocin, and a-Actinin-4 by immunoblot or by immunofluorescence (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In patients, MN-associated (autoantibody + /antigen + ) EVs fulfilled important features of exophers. As such, morphological criteria (extrusion from apical membranes especially from the juxtanuclear area as stalked large vesicles; expression of a characteristic set of EV markers) 18,20,21 , dynamic criteria (enhanced release by proteotoxic stress, reuptake by cells along the nephron) 18,27,34 , and molecular criteria (abundance of cell-specific and disease-associated proteins, presence of organelles) 18,35,22 establish them as a hitherto unrecognized podocyte-derived urinary EV form.…”

Section: Discussionmentioning

confidence: 99%

“…Exophers represent a novel type of extracellular vesicle (EV) recently discovered in Caenorhabditis elegans neurons 18 and body wall muscles 19 . Exophers extrude from juxtanuclear plasma membrane areas 20 as long nanotubules which can reach up to 4 µm in diameter at the distal end 21 . In C. elegans, exopherformation depends on cellular stressors 17,24 and mechanistically involves the delivery of cargo to aggresome-like organelles 20 .…”

Section: Introductionmentioning

confidence: 99%

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Podocyte exopher-formation as a novel pathomechanism in membranous nephropathy

Lahme,

Sachs,

Froembling

et al. 2024

Preprint

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Background: Membranous nephropathy (MN) is caused by autoantibody binding to podocyte foot process antigens such as THSD7A and PLA2R1. The mechanisms of the glomerular antigen/autoantibody deposition and clearance are unknown. Methods: We explore the origin and significance of glomerular accumulations in (1) diagnostic and follow-up biospecimens from THSD7A+ and PLA2R1+-MN patients compared to nephrotic non-MN patients, and (2) in experimental models of THSD7A+-MN. Results: We discovered podocyte exophers as correlates of histological antigen/autoantibody aggregates found in the glomerular urinary space of MN patients. Exopher vesicle formation represents a novel form of toxic protein aggregate removal in Caenorhabditis elegans neurons. In MN patients, podocytes released exophers to the urine. Enrichment of exophers from MN patient urines established them as a glomerular exit route for antigens and bound autoantibody. Exophers also carried disease-associated proteins such as complement and provided a molecular imprint of podocyte injury pathways. In experimental THSD7A+-MN, exophers were formed from podocyte processes and cell body. Their formation involved the translocation of antigen/autoantibody from the subepithelial to the urinary side of podocyte plasma membranes. Urinary exopher-release correlated with lower albuminuria and lower glomerular antigen/autoantibody burden. In MN patients the prospective monitoring of urinary exopher abundance and of exopher-bound autoantibodies was additive in the assessment of immunologic MN activity. Conclusions: Exopher-formation and release is a novel pathomechanism in MN to remove antigen/autoantibody aggregates from the podocyte. Tracking exopher-release will add a non-invasive diagnostic tool with prognostic potential to clinical diagnostics and follow-up of MN patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Podocyte exopher-formation as a novel pathomechanism in membranous nephropathy

Lahme,

Sachs,

Froembling

et al. 2024

Preprint

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show abstract

“…Exophers represent a novel type of extracellular vesicle (EV) recently discovered in Caenorhabditis elegans neurons 18 and body wall muscles 19 . Exophers extrude from juxtanuclear plasma membrane areas 20 as long nanotubules which can reach up to 4 µm in diameter at the distal end 21 . In C. elegans, exopher-formation depends on cellular stressors 17,24 and mechanistically involves the delivery of cargo to aggresome-like organelles 20 .…”

Section: Introductionmentioning

confidence: 99%

Podocyte exopher-formation as a novel pathomechanism in membranous nephropathy

Meyer-Schwesinger,

Lahme,

Sachs

et al. 2024

Preprint

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Background Membranous nephropathy (MN) is caused by autoantibody binding to podocyte foot process antigens such as THSD7A and PLA2R1. The mechanisms of the glomerular antigen/autoantibody deposition and clearance are unknown. Methods We explore the origin and significance of glomerular accumulations in (1) diagnostic and follow-up biospecimens from THSD7A+ and PLA2R1+-MN patients compared to nephrotic non-MN patients, and (2) in experimental models of THSD7A+-MN. Results We discovered podocyte exophers as correlates of histological antigen/autoantibody aggregates found in the glomerular urinary space of MN patients. Exopher vesicle formation represents a novel form of toxic protein aggregate removal in Caenorhabditis elegans neurons. In MN patients, podocytes released exophers to the urine. Enrichment of exophers from MN patient urines established them as a glomerular exit route for antigens and bound autoantibody. Exophers also carried disease-associated proteins such as complement and provided a molecular imprint of podocyte injury pathways. In experimental THSD7A+-MN, exophers were formed from podocyte processes and cell body. Their formation involved the translocation of antigen/autoantibody from the subepithelial to the urinary side of podocyte plasma membranes. Urinary exopher-release correlated with lower albuminuria and lower glomerular antigen/autoantibody burden. In MN patients the prospective monitoring of urinary exopher abundance and of exopher-bound autoantibodies was additive in the assessment of immunologic MN activity. Conclusions Exopher-formation and release is a novel pathomechanism in MN to remove antigen/autoantibody aggregates from the podocyte. Tracking exopher-release will add a non-invasive diagnostic tool with prognostic potential to clinical diagnostics and follow-up of MN patients.

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“…More specifically, C. elegans adult neurons can extrude large vesicles called exophers (~5µm, 100X larger than exosomes) that carry potentially deleterious proteins and organelles out of the neuron [3][4][5] .…”

Section: Introductionmentioning

confidence: 99%

Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

Wang,

Guasp,

Salam

et al. 2023

Preprint

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Large vesicle extrusion from neurons may contribute to spreading pathogenic protein aggregates and promoting inflammatory responses, two mechanisms leading to neurodegenerative disease. Factors that regulate extrusion of large vesicles, such as exophers produced by proteostressedC. eleganstouch neurons, are poorly understood. Here we document that mechanical force can significantly potentiate exopher extrusion from proteostressed neurons. Exopher production from theC. elegansALMR neuron peaks at adult day 2 or 3, coinciding with theC. elegansreproductive peak. Genetic disruption ofC. elegansgermline, sperm, oocytes, or egg/early embryo production can strongly suppress exopher extrusion from the ALMR neurons during the peak period. Conversely, restoring egg production at the late reproductive phase through mating with males or inducing egg retention via genetic interventions that block egg-laying can strongly increase ALMR exopher production. Overall, genetic interventions that promote ALMR exopher production are associated with expanded uterus lengths and genetic interventions that suppress ALMR exopher production are associated with shorter uterus lengths. In addition to the impact of fertilized eggs, ALMR exopher production can be enhanced by filling the uterus with oocytes, dead eggs, or even fluid, supporting that distention consequences, rather than the presence of fertilized eggs, constitute the exopher-inducing stimulus. We conclude that the mechanical force of uterine occupation potentiates exopher extrusion from proximal proteostressed maternal neurons. Our observations draw attention to the potential importance of mechanical signaling in extracellular vesicle production and in aggregate spreading mechanisms, making a case for enhanced attention to mechanobiology in neurodegenerative disease.

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Intermediate Filaments Associate with Aggresome-like Structures in ProteostressedC. elegansNeurons and Influence Large Vesicle Extrusions as Exophers

Cited by 3 publications

References 119 publications

Podocyte exopher-formation as a novel pathomechanism in membranous nephropathy

Podocyte exopher-formation as a novel pathomechanism in membranous nephropathy

Podocyte exopher-formation as a novel pathomechanism in membranous nephropathy

Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

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