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Proteotoxicity

About: Proteotoxicity is a research topic. Over the lifetime, 549 publications have been published within this topic receiving 23151 citations.


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Posted ContentDOI
25 Dec 2020-bioRxiv
TL;DR: It is concluded that the entire salvage NAD+ biosynthetic pathway links NAD+ metabolism and proteostasis and emerges as a target for therapeutics to combat age-associated neurodegenerative proteotoxicities.
Abstract: Human neurodegenerative proteinopathies are disorders associated with abnormal protein depositions in brain neurons. They include polyglutamine (polyQ) conditions such as Huntington9s disease (HD) and alpha-synucleinopathies such as Parkinson9s disease (PD). Overexpression of NMNAT/Nma1, an enzyme in the NAD+ biosynthetic salvage pathway, acts as an efficient suppressor of proteotoxicities in yeast, fly, and mouse models. Screens in yeast models of HD and PD allowed us to identify three additional enzymes of the same pathway that achieve similar protection against proteotoxic stress: Npt1, Pnc1, and Qns1. Here, we report that their ability to maintain proteostasis is independent of their catalytic activity and does not require cellular protein quality control systems such as the proteasome or autophagy. Furthermore, we show that, under proteotoxic stress, the four proteins are recruited as molecular chaperones with holdase and foldase activities. The NAD+ salvage proteins act by preventing misfolding and, together with the Hsp90 chaperone, promoting the refolding of extended polyQ domains or alpha-synuclein. We conclude that the entire salvage NAD+ biosynthetic pathway links NAD+ metabolism and proteostasis and emerges as a target for therapeutics to combat age-associated neurodegenerative proteotoxicities. Our observations also illustrate the existence of an evolutionarily conserved strategy of repurposing or moonlighting housekeeping enzymes under stress conditions to maintain proteostasis.

2 citations

Journal ArticleDOI
TL;DR: In this paper , perturbed proteostasis leading to compromised mitosis and meiosis in hybrid lines carrying one or two chromosomes from Saccharomyces bayanus var. uvarum was shown.
Abstract: Abstract Dobzhansky–Muller incompatibilities represent a major driver of reproductive isolation between species. They are caused when interacting components encoded by alleles from different species cannot function properly when mixed. At incipient stages of speciation, complex incompatibilities involving multiple genetic loci with weak effects are frequently observed, but the underlying mechanisms remain elusive. Here we show perturbed proteostasis leading to compromised mitosis and meiosis in Saccharomyces cerevisiae hybrid lines carrying one or two chromosomes from Saccharomyces bayanus var. uvarum . Levels of proteotoxicity are correlated with the number of protein complexes on replaced chromosomes. Proteomic approaches reveal that multi-protein complexes with subunits encoded by replaced chromosomes tend to be unstable. Furthermore, hybrid defects can be alleviated or aggravated, respectively, by up- or down-regulating the ubiquitin-proteasomal degradation machinery, suggesting that destabilized complex subunits overburden the proteostasis machinery and compromise hybrid fitness. Our findings reveal the general role of impaired protein complex assembly in complex incompatibilities.

2 citations

Journal ArticleDOI
31 Dec 2016
TL;DR: The present study unravels the anti-aging and stress modulatory potential of CO and suggests CO as a potential pharmaceutical entity in modulating aging process.
Abstract: Clove (Syzygium aromaticum) is a popular medicinal plant which has been traditionally used in India as spice and medicine to counter various ailments. However, the stress modulatory and antiaging potential of this plant is yet to be characterized. Therefore, the present study evaluates the effect of clove oil (CO) on oxidative stress, lifespan, mobility, and the expression of aging-related proteins using Caenorhabditis elegans model system. The CO (10 ppm) was found to extend mean lifespan in worms by 21.4% (p < 0.001) under normal and by 63% (p < 0.0001) under juglone-induced oxidative stress conditions. The extension of mean lifespan in mev-1 mutant and elevated expression of gst-4 and sod-3 confirmed stress modulatory effects of CO. Additionally, the CO reduced intracellular ROS and Aβ1–42 proteotoxicity. Altogether, the present study unravels the anti-aging and stress modulatory potential of CO and suggests CO as a potential pharmaceutical entity in modulating aging process.

2 citations

Journal ArticleDOI
TL;DR: The autophagy-lysosomal pathway (ALP) as discussed by the authors has been shown to be a valid therapeutic target for MNDs treatment focusing on traditional autoophagy modulators and emerging approaches to overcome their limitations.
Abstract: Motor neuron diseases (MNDs) include a broad group of diseases in which neurodegeneration mainly affects upper and/or lower motor neurons (MNs). Although the involvement of specific MNs, symptoms, age of onset, and progression differ in MNDs, the main pathogenic mechanism common to most MNDs is represented by proteostasis alteration and proteotoxicity. This pathomechanism may be directly related to mutations in genes encoding proteins involved in the protein quality control system, particularly the autophagy-lysosomal pathway (ALP). Alternatively, proteostasis alteration can be caused by aberrant proteins that tend to misfold and to aggregate, two related processes that, over time, cannot be properly handled by the ALP. Here, we summarize the main ALP features, focusing on different routes utilized to deliver substrates to the lysosome and how the various ALP pathways intersect with the intracellular trafficking of membranes and vesicles. Next, we provide an overview of the mutated genes that have been found associated with MNDs, how these gene products are involved in different steps of ALP and related processes. Finally, we discuss how autophagy can be considered a valid therapeutic target for MNDs treatment focusing on traditional autophagy modulators and on emerging approaches to overcome their limitations.

2 citations

Journal ArticleDOI
TL;DR: In this paper , aggregation of protein ectodomains triggers their endocytosis via a macro-endocytic route, and subsequent lysosomal degradation, which is an actin-driven process.
Abstract: Abstract The ability of cells to manage consequences of exogenous proteotoxicity is key to cellular homeostasis. While a plethora of well-characterised machinery aids intracellular proteostasis, mechanisms involved in the response to denaturation of extracellular proteins remain elusive. Here we show that aggregation of protein ectodomains triggers their endocytosis via a macroendocytic route, and subsequent lysosomal degradation. Using ERBB2/HER2-specific antibodies we reveal that their cross-linking ability triggers specific and fast endocytosis of the receptor, independent of clathrin and dynamin. Upon aggregation, canonical clathrin-dependent cargoes are redirected into the aggregation-dependent endocytosis (ADE) pathway. ADE is an actin-driven process, which morphologically resembles macropinocytosis. Physical and chemical stress-induced aggregation of surface proteins also triggers ADE, facilitating their degradation in the lysosome. This study pinpoints aggregation of extracellular domains as a trigger for rapid uptake and lysosomal clearance which besides its proteostatic function has potential implications for the uptake of pathological protein aggregates and antibody-based therapies.

2 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202327
202262
202166
202065
201950
201832