Mastering organismal aging through the endoplasmic reticulum proteostasis network

Taylor, Rebecca C.; Hetz, Claudio

doi:10.1111/acel.13265

Cited by 36 publications

(34 citation statements)

References 86 publications

(135 reference statements)

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“…This suggests that the combination of the Cdh23 753G→A mutation and Manf inactivation exceeds the critical threshold of ER stress above which OHC pathology ensues, leading to acceleration of age-related hearing loss. The capacity of the ER proteostasis network, including MANF as one of its components, has been shown to decline with ageing in tissues of both animals and humans ( Neves et al, 2016 ; Taylor & Hetz, 2020 ). This could be the case in the cochlear hair cells as well, and the down-regulation of MANF or components of the UPR could have an exacerbating effect on age-related progressive hearing loss.…”

Section: Discussionmentioning

confidence: 99%

“…The accumulation of misfolded proteins in the ER and the concomitant Ca 2+ release from the ER stores is termed as ER stress. It is emerging as a key driver of many human diseases, including diabetes and neurodegeneration (Hetz et al, 2020). ER proteostasis imbalance activates the unfolded protein response (UPR), a signalling cascade that mediates information about the protein folding status to the cytoplasm and nucleus, with the aim to initiate an adaptive or a proapoptotic stress response (Hetz et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…It is emerging as a key driver of many human diseases, including diabetes and neurodegeneration (Hetz et al, 2020). ER proteostasis imbalance activates the unfolded protein response (UPR), a signalling cascade that mediates information about the protein folding status to the cytoplasm and nucleus, with the aim to initiate an adaptive or a proapoptotic stress response (Hetz et al, 2020). MANF (mesencephalic astrocyte-derived neurotrophic factor) is an ER-resident protein that maintains normal ER homeostasis (Lindahl et al, 2014(Lindahl et al, , 2017Bell et al, 2019;Yan et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea

et al. 2021

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Failure in the structural maintenance of the hair cell stereocilia bundle and ribbon synapse causes hearing loss. Here, we have studied how ER stress elicits hair cell pathology, using mouse models with inactivation of Manf (mesencephalic astrocyte-derived neurotrophic factor), encoding an ER-homeostasis-promoting protein. From hearing onset, Manf deficiency caused disarray of the outer hair cell stereocilia bundle and reduced cochlear sound amplification capability throughout the tonotopic axis. In high-frequency outer hair cells, the pathology ended in molecular changes in the stereocilia taper region and in strong stereocilia fusion. In high-frequency inner hair cells, Manf deficiency degraded ribbon synapses. The altered phenotype strongly depended on the mouse genetic background. Altogether, the failure in the ER homeostasis maintenance induced early-onset stereociliopathy and synaptopathy and accelerated the effect of genetic causes driving age-related hearing loss. Correspondingly, MANF mutation in a human patient induced severe sensorineural hearing loss from a young age onward. Thus, we present MANF as a novel protein and ER stress as a mechanism that regulate auditory hair cell maintenance in both mice and humans.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea

et al. 2021

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“…At the same time, enhanced lipid biogenesis increases protein folding and protein degradation in the ER ( Chalmers et al, 2017 ; Frakes and Dillin, 2017 ). However, the ability to induce the UPR ER and its downstream targets decline with increasing age ( Sabath et al, 2020 ; Taylor and Hetz, 2020 ). In addition, absolute UPR ER -induced chaperone levels decrease during aging and the UPR ER -regulated chaperones that are still present, accumulate increasing amounts of oxidative damage ( Taylor, 2016 ).…”

Section: Protein Homeostasis Declines With Agingmentioning

confidence: 99%

“…In addition, absolute UPR ER -induced chaperone levels decrease during aging and the UPR ER -regulated chaperones that are still present, accumulate increasing amounts of oxidative damage ( Taylor, 2016 ). The role of UPR ER in aging has recently been extensively reviewed by Taylor and Hetz ( Taylor and Hetz, 2020 ).…”

Section: Protein Homeostasis Declines With Agingmentioning

confidence: 99%

Regulation of Age-Related Protein Toxicity

Pras

Nollen

2021

Front. Cell Dev. Biol.

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Proteome damage plays a major role in aging and age-related neurodegenerative diseases. Under healthy conditions, molecular quality control mechanisms prevent toxic protein misfolding and aggregation. These mechanisms include molecular chaperones for protein folding, spatial compartmentalization for sequestration, and degradation pathways for the removal of harmful proteins. These mechanisms decline with age, resulting in the accumulation of aggregation-prone proteins that are harmful to cells. In the past decades, a variety of fast- and slow-aging model organisms have been used to investigate the biological mechanisms that accelerate or prevent such protein toxicity. In this review, we describe the most important mechanisms that are required for maintaining a healthy proteome. We describe how these mechanisms decline during aging and lead to toxic protein misassembly, aggregation, and amyloid formation. In addition, we discuss how optimized protein homeostasis mechanisms in long-living animals contribute to prolonging their lifespan. This knowledge might help us to develop interventions in the protein homeostasis network that delay aging and age-related pathologies.

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The role of NAD and NAD precursors on longevity and lifespan modulation in the budding yeast, Saccharomyces cerevisiae

et al. 2022

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Molecular causes of aging and longevity interventions have witnessed an upsurge in the last decade. The resurgent interests in the application of small molecules as potential geroprotectors and/or pharmacogenomics point to nicotinamide adenine dinucleotide (NAD) and its precursors, nicotinamide riboside, nicotinamide mononucleotide, nicotinamide, and nicotinic acid as potentially intriguing molecules. Upon supplementation, these compounds have shown to ameliorate aging related conditions and possibly prevent death in model organisms. Besides being a molecule essential in all living cells, our understanding of the mechanism of NAD metabolism and its regulation remain incomplete owing to its omnipresent nature. Here we discuss recent advances and techniques in the study of chronological lifespan (CLS) and replicative lifespan (RLS) in the model unicellular organism Saccharomyces cerevisiae . We then follow with the mechanism and biology of NAD precursors and their roles in aging and longevity. Finally, we review potential biotechnological applications through engineering of microbial lifespan, and laid perspective on the promising candidature of alternative redox compounds for extending lifespan.

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Mastering organismal aging through the endoplasmic reticulum proteostasis network

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 36 publications

References 86 publications

MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea

MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea

Regulation of Age-Related Protein Toxicity

The role of NAD and NAD precursors on longevity and lifespan modulation in the budding yeast, Saccharomyces cerevisiae

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