Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in Caenorhabditis elegans

Huang, Chaolie; Wagner-Valladolid, Sara; Stephens, Amberley D.; Jung, Raimund; Poudel, Chetan; Sinnige, Tessa; Lechler, Marie C.; Schlörit, Nicole; Lü, Meng; Laine, Romain F.; Michel, Claire H.; Vendruscolo, Michele; Kaminski, Clemens F.; Schierle, Gabriele S Kaminski; David, Della

doi:10.7554/elife.43059

Cited by 60 publications

(88 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have shown that protein aggregation accelerates the functional decline of different tissues [49]. In support of this idea, we detected a marked increase in protein aggregation in lung fibroblasts of IPF and chronically injured mice and this finding was associated with increases in cellular senescence and myofibroblast activation markers.…”

Section: Discussionsupporting

confidence: 88%

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Cuevas-Mora

Roque

Sales

et al. 2020

Preprint

View full text Add to dashboard Cite

Loss of proteostasis and cellular senescence are key hallmarks of aging. Recent studies suggest that lung fibroblasts from idiopathic pulmonary fibrosis (IPF) show features of cellular senescence, decline in heat shock proteins (HSPs) expression and impaired protein homeostasis (proteostasis). However, direct cause-effect relationships are still mostly unknown. In this study, we sought to investigate whether the heat shock factor 1 (HSF1), a major transcription factor that regulates the cellular HSPs network and cytoplasmic proteostasis, contributes to cellular senescence in lung fibroblasts. We found that IPF lung fibroblasts showed an upregulation in the expression of various cellular senescence markers, including β -galactosidase activity (SA-β-gal) staining, the DNA damage marker γ H2Ax, the cell cycle inhibitor protein p21, and multiple senescence-associated secretory proteins (SASP), as well as upregulation of collagen 1a1, fibronectin and alpha-smooth muscle actin (α-SMA) gene expression compared with age-matched controls. These changes were associated with impaired proteostasis, as judged by an increase in levels of p-HSF1 ser307 and HSF1 K298 sumo , downregulation of HSPs expression, and increased cellular protein aggregation. Similarly, lung fibroblasts isolated from a mouse model of bleomycin-induced lung fibrosis and mouse lung fibroblast chronically treated with H 2 O 2 showed downregulation in HSPs and increased in cellular senescence and SASP markers. Moreover, sustained pharmacologic activation of HSF1 increased the expression of HSPs, reduced cellular senescence markers and effectively reduced the expression of pro-fibrotic genes in IPF fibroblast. Our data provide evidence that the HSF1-mediated proteostasis is important for driving lung fibroblasts toward cellular senescence and a myofibroblast phenotype. We postulate that enhancing HSF1 activity could be effective in the treatment of lung fibrosis. METHODSAnimals. C57B/6J mice (8-10 weeks old) were purchased from the Jackson Laboratory (Bar Harbor, ME) and housed in a pathogen-free animal facility at Thomas Jefferson University. Throughout the study period, mice were maintained on a standard chow diet (13.5% calories from fat, 58% from carbohydrates, and 28.5% from protein) and permitted to feed ad libitum. ). They were isolated from the uninvolved periphery of the organ of six lung cancer patients. Fresh tissues were transported immediately to the laboratory for isolating fibroblasts according to procedures described before [35].Bleomycin-induced lung injury: Bleomycin sulphate (Enzo life science, BML-AP302-0050) was dissolved in phosphate buffered saline. Lung injury was induced by instilling 0.04U of bleomycin into the posterior oropharynx of anesthetized mice every other week for five doses [36]. The mice were observed following intubation to ensure complete recovery from anesthesia. Mice were euthanized 2 weeks after the last dose by exposure to carbon dioxide, and lungs were harvested for fibroblast isolation and histological preparation...

show abstract

Section: Discussionsupporting

confidence: 88%

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Cuevas-Mora

Roque

Sales

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Of note, the core region of some large aggregates was refractory to photoconversion ( Fig. 2 and as previously described [22]). Thereafter, we followed the rate of new (green emitting) aggregate formation and the rate of old (red emitting) aggregate removal over time.…”

Section: Sapa Prevents De Novo Formation Of Aggregatessupporting

confidence: 71%

“…PAB-1 contains a low complexity prion-like domain and undergoes liquid-liquid phase separation to form stress granules, putting it at risk of aggregating during aging or chronic stress in C. elegans [23,38]. In contrast, both KIN-19 and RHO-1 are highly structured globular proteins, which are intrinsically prone to aggregate shortly after synthesis [22]. Notably, the divergent aggregation processes are controlled by different mechanisms [23,38,39].…”

Section: Sapa Displays Aggregation-prone Substrate Specificitymentioning

confidence: 99%

“…With the concomitant decline in proteostasis during aging, the intrinsic aggregation propensity of part of the proteome becomes a challenge for the organism [10][11][12] and widespread protein aggregation is found in aged animals of different species [5,[13][14][15][16][17][18][19][20][21]. Agedependent aggregates show similarities to disease-associated protein aggregates and contain amyloid-like structures [18,22]. Notably, evidence from the model organism Caenorhabditis elegans reveals that age-dependent aggregates are toxic and accelerate the functional decline of tissues [22,23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tissue-specific safety mechanism results in opposite protein aggregation patterns during aging

Jung

Lechler

Rödelsperger

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

During aging, proteostasis capacity declines and aggregation-prone proteins become instable, accumulating in protein aggregates both inside and outside cells. Both in disease and during aging, proteins selectively aggregate in certain tissues and not others. Yet, tissue-specific regulation of protein aggregation remains poorly understood. Surprisingly, we found that the inhibition of three core protein quality control systems, i.e. chaperones, proteasome and macroautophagy, leads to lower levels of age-dependent protein aggregation in C. elegans pharyngeal muscles, but higher levels in body-wall muscles. We describe a novel safety mechanism called SAPA that selectively targets newly synthesized aggregation-prone proteins to suppress aggregation and proteotoxicity. vha-12 and scav-3 mutants reveal that SAPA relies on macroautophagy-independent lysosomal degradation. Furthermore, SAPA involves several previously uncharacterized components of the intracellular pathogen response. We propose that SAPA represents an anti-aggregation machinery targeting aggregation-prone proteins for lysosomal degradation.

show abstract

“…FUS501 aggregation may also promote aggregation of other proteins. It is well established that the C. elegans intracellular environment becomes more prone to aggregation across ageing, and this is exacerbated by the overexpression of aggregation-prone proteins (David et al, 2010; Huang et al, 2019; Walther et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

An ALS-associated mutation in human FUS reduces neurotransmission fromC. elegansmotor neurons to muscles

Markert

Skoruppa

et al. 2019

Preprint

View full text Add to dashboard Cite

Amytrophic lateral sclerosis (ALS) is a neurodegenerative disorder that has been associated with multiple genetic lesions, including mutations in the gene FUS (Fused in Sarcoma), an RNA/DNA-binding protein. Expression of the ALS-associated human FUS in C. elegans results in mislocalization and aggregation of FUS outside the nucleus, and leads to impaired neuromuscular behaviors. However, the mechanisms by which mutant FUS disrupts neuronal health and function remain partially understood. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. Expression of ALS-associated FUS impairs synaptic vesicle docking at neuromuscular junctions, and leads to the emergence of a population of large and electron-dense filament-filled endosomes. Electrophysiological recording of neuromuscular transmission revealed reduced transmission from motor neurons to muscles. Together, these results suggest a potential direct or indirect role of human FUS in the organization of synaptic vesicles, and reduced transmission from motor neurons to muscles. Summary statement An ALS-associated mutation in a trafficking protein disrupts the organization of the C. elegans neuromuscular junction.

show abstract

Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in Caenorhabditis elegans

Cited by 60 publications

References 73 publications

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Tissue-specific safety mechanism results in opposite protein aggregation patterns during aging

An ALS-associated mutation in human FUS reduces neurotransmission fromC. elegansmotor neurons to muscles

Contact Info

Product

Resources

About