scholarly journals A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yifei Zhou ◽  
Xueqing Wang ◽  
Mengjiao Song ◽  
Zhidong He ◽  
Guizhong Cui ◽  
...  
Keyword(s):  
Quality Control ◽  
Caenorhabditis Elegans ◽  
Extracellular Vesicles ◽  
Body Wall ◽  
Protein Quality ◽  
Protein Quality Control ◽  
The Body ◽  
Protein Homeostasis ◽  
Age Related ◽  
Different Tissues

Abstract Macroautophagy, a key player in protein quality control, is proposed to be systematically impaired in distinct tissues and causes coordinated disruption of protein homeostasis and ageing throughout the body. Although tissue-specific changes in autophagy and ageing have been extensively explored, the mechanism underlying the inter-tissue regulation of autophagy with ageing is poorly understood. Here, we show that a secreted microRNA, mir-83/miR-29, controls the age-related decrease in macroautophagy across tissues in Caenorhabditis elegans. Upregulated in the intestine by hsf-1/HSF1 with age, mir-83 is transported across tissues potentially via extracellular vesicles and disrupts macroautophagy by suppressing CUP-5/MCOLN, a vital autophagy regulator, autonomously in the intestine as well as non-autonomously in body wall muscle. Mutating mir-83 thereby enhances macroautophagy in different tissues, promoting protein homeostasis and longevity. These findings thus identify a microRNA-based mechanism to coordinate the decreasing macroautophagy in various tissues with age.

scholarly journals Protein quality control: from mechanism to disease

2019 ◽  
Vol 24 (6) ◽  
pp. 1013-1026
Author(s):  
Harm H. Kampinga ◽  
Matthias P. Mayer ◽  
Axel Mogk
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Acute Stress ◽  
Protein Quality Control ◽  
Cellular Protein ◽  
Stress Conditions ◽  
Protein Homeostasis ◽  
Physiological Conditions ◽  
Age Related ◽  
Medical Translation

Abstract The cellular protein quality control machinery with its central constituents of chaperones and proteases is vital to maintain protein homeostasis under physiological conditions and to protect against acute stress conditions. Imbalances in protein homeostasis also are keys to a plethora of genetic and acquired, often age-related, diseases as well as aging in general. At the EMBO Workshop, speakers covered all major aspects of cellular protein quality control, from basic mechanisms at the molecular, cellular, and organismal level to medical translation. In this report, the highlights of the meeting will be summarized.

scholarly journals Spatial protein quality control and the evolution of lineage-specific ageing

2011 ◽  
Vol 366 (1561) ◽  
pp. 71-75 ◽  
Author(s):  
Thomas Nyström
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Division Of Labour ◽  
Cell Renewal ◽  
Periodic Cell ◽  
Age Related ◽  
Selective Forces ◽  
Rate Of Ageing ◽  
Protein Folding Disorders

Propagation of a species requires periodic cell renewal to avoid clonal extinction. Sexual reproduction and the separation of germ cells from the soma provide a mechanism for such renewal, but are accompanied by an apparently mandatory ageing of the soma. Data obtained during the last decade suggest that a division of labour exists also between cells of vegetatively reproducing unicellular organisms, leading to the establishment of a soma-like and germ-like lineage with distinct fitness and longevity characteristics. This division of labour in both bacteria and yeast entails segregation of damaged and aggregated proteins such that the germ-like lineage is kept free of damage to the detriment of the soma-like lineage. In yeast, this spatial protein quality control (SQC) encompasses a CCT-chaperonin-dependent translocation and merging of cytotoxic protein aggregates. This process is regulated by Sir2, a protein deacetylase that modulates the rate of ageing in organisms ranging from yeast to worms and flies. Recent data also demonstrate that SQC is intimately integrated with the machinery establishing proper cell polarity and that this machinery is required for generating a soma-like and germ-like lineage in yeast. Deciphering the details of the SQC network may increase our understanding of the development of age-related protein folding disorders and shed light on the selective forces that paved the way for polarity and lineage-specific ageing to evolve.

The role of protein quality control in mitochondrial protein homeostasis under oxidative stress

PROTEOMICS ◽  
2010 ◽  
Vol 10 (7) ◽  
pp. 1426-1443 ◽  
Author(s):  
Tom Bender ◽  
Claudia Leidhold ◽  
Thomas Ruppert ◽  
Sebastian Franken ◽  
Wolfgang Voos
Keyword(s):  
Oxidative Stress ◽  
Quality Control ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Protein Homeostasis

scholarly journals Oxidative Stress and Protein Quality Control Systems in the Aged Canine Brain as a Model for Human Neurodegenerative Disorders

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Mariarita Romanucci ◽  
Leonardo Della Salda
Keyword(s):  
Quality Control ◽  
Control Systems ◽  
Protein Quality ◽  
Treatment Strategies ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Canine Model ◽  
Canine Brain ◽  
Age Related ◽  
Novel Treatment Strategies

Aged dogs are considered the most suitable spontaneous animal model for studying normal aging and neurodegenerative diseases. Elderly canines naturally develop cognitive dysfunction and neuropathological hallmarks similar to those seen in humans, especially Alzheimer’s disease-like pathology. Pet dogs also share similar living conditions and diets to humans. Oxidative damage accumulates in the canine brain during aging, making dogs a valid model for translational antioxidant treatment/prevention studies. Evidence suggests the presence of detective protein quality control systems, involving ubiquitin-proteasome system (UPS) and Heat Shock Proteins (HSPs), in the aged canine brain. Further studies on the canine model are needed to clarify the role of age-related changes in UPS activity and HSP expression in neurodegeneration in order to design novel treatment strategies, such as HSP-based therapies, aimed at improving chaperone defences against proteotoxic stress affecting brain during aging.

scholarly journals Mechanismen und Funktionen von bakteriellen AAA+­Entfaltungsmaschinen

BIOspektrum ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 22-24
Author(s):  
Axel Mogk
Keyword(s):  
Quality Control ◽  
Drug Target ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Stress Conditions ◽  
Misfolded Proteins ◽  
Antibacterial Drug ◽  
Protein Homeostasis ◽  
Antibacterial Drug Target

AbstractBacterial AAA+ proteins play crucial roles in proteostasis networks and ensure protein homeostasis during stress conditions. They function as ATP-dependent components of proteolytic complexes degrading misfolded proteins or as disaggregases reactivating aggregated proteins. AAA+ proteins generate an ATP-fueled threading force driving substrate unfolding and translocation. Their central functions in protein quality control qualify them as antibacterial drug target.

scholarly journals Novel proteostasis reporter mouse reveals different effects of cytoplasmic and nuclear aggregates on protein quality control in neurons

2020 ◽  
Author(s):  
Sonja Blumenstock ◽  
Elena Katharina Schulz-Trieglaff ◽  
Anna-Lena Bolender ◽  
Kerstin Voelkl ◽  
Paul Lapios ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Cellular Protein ◽  
Aging Brain ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures ◽  
Age Related ◽  
Reporter Mice

AbstractThe cellular protein quality control machinery is important for preventing protein misfolding and aggregation, and decline in protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how proteostasis capacity of neurons changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc), a conformationally unstable protein that requires chaperones for proper folding and sensitively reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked impairment in proteostasis in tauopathy mice, but not in Huntington’s disease mice. Mechanistic investigations in primary neuronal cultures demonstrate that cytoplasmic, but not nuclear, aggregates cause defects of cellular protein quality control. Thus, the Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

scholarly journals Structure, dynamics and functions of UBQLNs: at the crossroads of protein quality control machinery

2020 ◽  
Vol 477 (18) ◽  
pp. 3471-3497 ◽  
Author(s):  
Tongyin Zheng ◽  
Yiran Yang ◽  
Carlos A. Castañeda
Keyword(s):  
Quality Control ◽  
Rna Binding ◽  
Protein Quality ◽  
Rna Binding Proteins ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
Intrinsically Disordered ◽  
Structure Dynamics ◽  
And Function

Cells rely on protein homeostasis to maintain proper biological functions. Dysregulation of protein homeostasis contributes to the pathogenesis of many neurodegenerative diseases and cancers. Ubiquilins (UBQLNs) are versatile proteins that engage with many components of protein quality control (PQC) machinery in cells. Disease-linked mutations of UBQLNs are most commonly associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. UBQLNs play well-established roles in PQC processes, including facilitating degradation of substrates through the ubiquitin–proteasome system (UPS), autophagy, and endoplasmic-reticulum-associated protein degradation (ERAD) pathways. In addition, UBQLNs engage with chaperones to sequester, degrade, or assist repair of misfolded client proteins. Furthermore, UBQLNs regulate DNA damage repair mechanisms, interact with RNA-binding proteins (RBPs), and engage with cytoskeletal elements to regulate cell differentiation and development. Important to the myriad functions of UBQLNs are its multidomain architecture and ability to self-associate. UBQLNs are linked to numerous types of cellular puncta, including stress-induced biomolecular condensates, autophagosomes, aggresomes, and aggregates. In this review, we focus on deciphering how UBQLNs function on a molecular level. We examine the properties of oligomerization-driven interactions among the structured and intrinsically disordered segments of UBQLNs. These interactions, together with the knowledge from studies of disease-linked mutations, provide significant insights to UBQLN structure, dynamics and function.

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