scholarly journals Centrosome-phagy: implications for human diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qi Wu ◽  
Xin Yu ◽  
Le Liu ◽  
Shengrong Sun ◽  
Si Sun
Keyword(s):  
Human Diseases ◽  
Proliferating Cells ◽  
Molecular Systems ◽  
Subcellular Compartments ◽  
Human Disorders ◽  
Autophagic Degradation ◽  
Specific Degradation ◽  
Centrosomal Proteins

AbstractAutophagy is a prominent mechanism to preserve homeostasis and the response to intracellular or extracellular stress. Autophagic degradation can be selectively targeted to dysfunctional subcellular compartments. Centrosome homeostasis is pivotal for healthy proliferating cells, but centrosome aberration is a hallmark of diverse human disorders. Recently, a process called centrosome-phagy has been identified. The process involves a panel of centrosomal proteins and centrosome-related pathways that mediate the specific degradation of centrosomal components via the autophagic machinery. Although autophagy normally mediates centrosome homeostasis, autophagy defects facilitate ageing and multiple human diseases, such as ciliopathies and cancer, which benefit from centrosome aberration. Here, we discuss the molecular systems that trigger centrosome-phagy and its role in human disorders.

scholarly journals From purines to purinergic signalling: molecular functions and human diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhao Huang ◽  
Na Xie ◽  
Peter Illes ◽  
Francesco Di Virgilio ◽  
Henning Ulrich ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Healthy Lifestyle ◽  
Therapeutic Potential ◽  
Purine Metabolism ◽  
Human Diseases ◽  
Proper Function ◽  
Purinergic Signalling ◽  
Nucleotide Synthesis ◽  
Metabolism Disorder ◽  
Human Disorders

AbstractPurines and their derivatives, most notably adenosine and ATP, are the key molecules controlling intracellular energy homoeostasis and nucleotide synthesis. Besides, these purines support, as chemical messengers, purinergic transmission throughout tissues and species. Purines act as endogenous ligands that bind to and activate plasmalemmal purinoceptors, which mediate extracellular communication referred to as “purinergic signalling”. Purinergic signalling is cross-linked with other transmitter networks to coordinate numerous aspects of cell behaviour such as proliferation, differentiation, migration, apoptosis and other physiological processes critical for the proper function of organisms. Pathological deregulation of purinergic signalling contributes to various diseases including neurodegeneration, rheumatic immune diseases, inflammation, and cancer. Particularly, gout is one of the most prevalent purine-related disease caused by purine metabolism disorder and consequent hyperuricemia. Compelling evidence indicates that purinoceptors are potential therapeutic targets, with specific purinergic agonists and antagonists demonstrating prominent therapeutic potential. Furthermore, dietary and herbal interventions help to restore and balance purine metabolism, thus addressing the importance of a healthy lifestyle in the prevention and relief of human disorders. Profound understanding of molecular mechanisms of purinergic signalling provides new and exciting insights into the treatment of human diseases.

scholarly journals NudCL2 is an autophagy receptor that mediates selective autophagic degradation of CP110 at mother centrioles to promote ciliogenesis

Cell Research ◽  
2021 ◽  
Author(s):  
Min Liu ◽  
Wen Zhang ◽  
Min Li ◽  
Jiaxing Feng ◽  
Wenjun Kuang ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Coiled Coil ◽  
Serum Starvation ◽  
Vertebrate Development ◽  
Wild Type ◽  
Selective Degradation ◽  
Mother Centriole ◽  
Autophagic Degradation ◽  
Specific Degradation ◽  
Lir Motif

AbstractPrimary cilia extending from mother centrioles are essential for vertebrate development and homeostasis maintenance. Centriolar coiled-coil protein 110 (CP110) has been reported to suppress ciliogenesis initiation by capping the distal ends of mother centrioles. However, the mechanism underlying the specific degradation of mother centriole-capping CP110 to promote cilia initiation remains unknown. Here, we find that autophagy is crucial for CP110 degradation at mother centrioles after serum starvation in MEF cells. We further identify NudC-like protein 2 (NudCL2) as a novel selective autophagy receptor at mother centrioles, which contains an LC3-interacting region (LIR) motif mediating the association of CP110 and the autophagosome marker LC3. Knockout of NudCL2 induces defects in the removal of CP110 from mother centrioles and ciliogenesis, which are rescued by wild-type NudCL2 but not its LIR motif mutant. Knockdown of CP110 significantly attenuates ciliogenesis defects in NudCL2-deficient cells. In addition, NudCL2 morphants exhibit ciliation-related phenotypes in zebrafish, which are reversed by wild-type NudCL2, but not its LIR motif mutant. Importantly, CP110 depletion significantly reverses these ciliary phenotypes in NudCL2 morphants. Taken together, our data suggest that NudCL2 functions as an autophagy receptor mediating the selective degradation of mother centriole-capping CP110 to promote ciliogenesis, which is indispensable for embryo development in vertebrates.

scholarly journals Designing peptide drug with archaeal antimicrobial peptides against multidrug resistant bacterial biofilms and human diseases: an in silico approach

2021 ◽  
Author(s):  
SOUVIK BANERJEE ◽  
SOHAM CHAKRABORTY ◽  
KAUSTAV MAJUMDER
Keyword(s):  
Antimicrobial Peptides ◽  
In Silico ◽  
Conformational Dynamics ◽  
Multidrug Resistant ◽  
Human Diseases ◽  
Bacterial Biofilms ◽  
In Silico Docking ◽  
Human Disorders ◽  
The Moment

The adverse role of multi-drug resistant bacterial biofilms accelerating human chronic diseases has posed a great risk to present world. Devising a therapy to impede such perilous effects is the need of the moment. So, in this study, we have designed a novel peptide therapy involving archaeal antimicrobial peptides. In silico predictions assign the peptide construct to be antigenic, non-allergenic, anti-cancerous and having stable physicochemical properties. Computational tools predict intracellular receptors in Escherichia coli and human to be possible binding targets of the construct. In silico docking of modelled peptide with targets, validated the predicted estimations. Coincidentally few human receptors binding strongly to the peptide, tend to be the widely recognized targets associated to human diseases with severe complications. Studies of conformational dynamics of peptide docked complexes with human and bacterial targets, indicated stable binding of the modelled construct. Certainly, the designed peptide could be a potent therapeutic against biofilms and human disorders.

scholarly journals Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Elisa Gorostieta-Salas ◽  
Daniel Moreno-Blas ◽  
Cristian Gerónimo-Olvera ◽  
Bulmaro Cisneros ◽  
Felipe A. Court ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Brain Aging ◽  
Autophagic Flux ◽  
Proliferating Cells ◽  
Neuronal Homeostasis ◽  
Autophagic Degradation ◽  
Vitro Model ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Brain aging is characterized by dysfunctional autophagy and cellular senescence, among other features. While autophagy can either promote or suppress cellular senescence in proliferating cells, in postmitotic cells, such as neurons, autophagy impairment promotes cellular senescence. CRM1 (exportin-1/XPO1) exports hundreds of nuclear proteins into the cytoplasm, including the transcription factors TFEB (the main inducer of autophagy and lysosomal biogenesis genes) and STAT3, another autophagy modulator. It appears that CRM1 is a modulator of aging-associated senescence and autophagy, because pharmacological inhibition of CRM1 improved autophagic degradation in flies, by increasing nuclear TFEB levels, and because enhanced CRM1 activity is mechanistically linked to senescence in fibroblasts from Hutchinson–Gilford progeria syndrome patients and old healthy individuals; furthermore, the exogenous overexpression of CRM1 induced senescence in normal fibroblasts. In this work, we tested the hypothesis that impaired autophagic flux during brain aging occurs due to CRM1 accumulation in the brain. We found that CRM1 levels and activity increased in the hippocampus and cortex during physiological aging, which resulted in a decrease of nuclear TFEB and STAT3. Consistent with an autophagic flux impairment, we observed accumulation of the autophagic receptor p62/SQSTM1 in neurons of old mice, which correlated with increased neuronal senescence. Using an in vitro model of neuronal senescence, we demonstrate that CRM1 inhibition improved autophagy flux and reduced SA-β-gal activity by restoring TFEB nuclear localization. Collectively, our data suggest that enhanced CRM1-mediated export of proteins during brain aging perturbs neuronal homeostasis, contributing to autophagy impairment, and neuronal senescence.

scholarly journals Fishing in the Cell Powerhouse: Zebrafish as A Tool for Exploration of Mitochondrial Defects Affecting the Nervous System

2019 ◽  
Vol 20 (10) ◽  
pp. 2409 ◽  
Author(s):  
Gianluca Fichi ◽  
Valentina Naef ◽  
Amilcare Barca ◽  
Giovanna Longo ◽  
Baldassare Fronte ◽  
...  
Keyword(s):  
Nervous System ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Human Diseases ◽  
Energy Output ◽  
Limited Attention ◽  
Large Numbers ◽  
Human Disorders ◽  
Mitochondrial Defects ◽  
Small Vertebrate

The zebrafish (Danio rerio) is a small vertebrate ideally suited to the modeling of human diseases. Large numbers of genetic alterations have now been modeled and could be used to study organ development by means of a genetic approach. To date, limited attention has been paid to the possible use of the zebrafish toolbox in studying human mitochondrial disorders affecting the nervous system. Here, we review the pertinent scientific literature discussing the use of zebrafish in modeling gene mutations involved in mitochondria-related neurological human diseases. A critical analysis of the literature suggests that the zebrafish not only lends itself to exploration of the pathological consequences of mitochondrial energy output on the nervous system but could also serve as an attractive platform for future drugs in an as yet untreatable category of human disorders.

scholarly journals The CP110-CEP97-CEP290 module orchestrates a centriolar satellite dependent response to proteotoxic stress

2020 ◽  
Author(s):  
Suzanna L. Prosser ◽  
Johnny Tkach ◽  
Ladan Gheiratmand ◽  
Ciaran G. Morrison ◽  
Laurence Pelletier
Keyword(s):  
Quantitative Analysis ◽  
Ubiquitin Proteasome System ◽  
Mutant Huntingtin ◽  
Cellular Processes ◽  
Proteotoxic Stress ◽  
Human Disorders ◽  
Ubiquitin Proteasome ◽  
Microscopy Analysis ◽  
Aggresome Formation ◽  
Centrosomal Proteins

ABSTRACTProtein degradation at the centrosome, the primary microtubule organizing centre of the cell, is critical to a myriad of cellular processes. Perturbation of the ubiquitin proteasome system causes the formation of an inclusion, or aggresome, at the centrosome. By systematic microscopy analysis, we have placed a subset of centrosomal proteins within the aggresome. Centriolar satellites, proteinaceous granules found in the vicinity of centrosomes, also became incorporated into this structure. Through high-resolution quantitative analysis, we have defined aggresome assembly at the centrosome, demonstrating a requirement for satellites in this process. Furthermore, a module consisting of CP110-CEP97-CEP290 was required to recruit aggresome components early in the pathway and senescent cells were defective in aggresome formation due to limiting amounts of CP110. Finally, satellites and the CP110-CEP97-CEP290 module were required for the aggregation of mutant huntingtin. The accumulation of protein aggregates is central to the pathology of a range of human disorders. These data thereby reveal new roles for CP110, its interactors, and centriolar satellites in controlling cellular proteostasis and the aggregation of disease relevant proteins.

scholarly journals Pathophysiological Significance of WDR62 and JNK Signaling in Human Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Yiqiang Zhi ◽  
Xiaokun Zhou ◽  
Jurui Yu ◽  
Ling Yuan ◽  
Hongsheng Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Neurological Disorders ◽  
Therapeutic Strategy ◽  
Human Diseases ◽  
Wd40 Repeat ◽  
Jnk Signaling ◽  
Evolutionarily Conserved ◽  
Human Disorders ◽  
Jnk Signaling Pathway ◽  
Cell Mitosis

The c-Jun N-terminal kinase (JNK) is highly evolutionarily conserved and plays important roles in a broad range of physiological and pathological processes. The WD40-repeat protein 62 (WDR62) is a scaffold protein that recruits different components of the JNK signaling pathway to regulate several human diseases including neurological disorders, infertility, and tumorigenesis. Recent studies revealed that WDR62 regulates the process of neural stem cell mitosis and germ cell meiosis through JNK signaling. In this review we summarize the roles of WDR62 and JNK signaling in neuronal and non-neuronal contexts and discuss how JNK-dependent signaling regulates both processes. WDR62 is involved in various human disorders via JNK signaling regulation, and may represent a promising therapeutic strategy for the treatment of related diseases.

scholarly journals Zebrafish, an In Vivo Platform to Screen Drugs and Proteins for Biomedical Use

2021 ◽  
Vol 14 (6) ◽  
pp. 500
Author(s):  
Hung-Chieh Lee ◽  
Cheng-Yung Lin ◽  
Huai-Jen Tsai
Keyword(s):  
Drug Screening ◽  
Human Genetics ◽  
Environmental Pollutant ◽  
Human Diseases ◽  
Dravet Syndrome ◽  
Lower Vertebrate ◽  
High Fecundity ◽  
Human Disorders

The nearly simultaneous convergence of human genetics and advanced molecular technologies has led to an improved understanding of human diseases. At the same time, the demand for drug screening and gene function identification has also increased, albeit time- and labor-intensive. However, bridging the gap between in vitro evidence from cell lines and in vivo evidence, the lower vertebrate zebrafish possesses many advantages over higher vertebrates, such as low maintenance, high fecundity, light-induced spawning, transparent embryos, short generation interval, rapid embryonic development, fully sequenced genome, and some phenotypes similar to human diseases. Such merits have popularized the zebrafish as a model system for biomedical and pharmaceutical studies, including drug screening. Here, we reviewed the various ways in which zebrafish serve as an in vivo platform to perform drug and protein screening in the fields of rare human diseases, social behavior and cancer studies. Since zebrafish mutations faithfully phenocopy many human disorders, many compounds identified from zebrafish screening systems have advanced to early clinical trials, such as those for Adenoid cystic carcinoma, Dravet syndrome and Diamond–Blackfan anemia. We also reviewed and described how zebrafish are used to carry out environmental pollutant detection and assessment of nanoparticle biosafety and QT prolongation.

scholarly journals Probing the mechanisms underlying human diseases in making ribosomes

2016 ◽  
Vol 44 (4) ◽  
pp. 1035-1044 ◽  
Author(s):  
Katherine I. Farley ◽  
Susan J. Baserga
Keyword(s):  
Protein Synthesis ◽  
Ribosome Biogenesis ◽  
Human Cells ◽  
Human Diseases ◽  
Tissue Specific ◽  
Ribosome Synthesis ◽  
Human Disorders ◽  
Specific Disorders

Ribosomes are essential, highly complex machines responsible for protein synthesis in all growing cells. Because of their importance, the process of building these machines is intricately regulated. Although the proteins involved in regulating ribosome biogenesis are just beginning to be understood, especially in human cells, the consequences for dysregulating this process have been even less studied. Such interruptions in ribosome synthesis result in a collection of human disorders known as ribosomopathies. Ribosomopathies, which occur due to mutations in proteins involved in the global process of ribosome biogenesis, result in tissue-specific defects. The questions posed by this dichotomy and the steps taken to address these questions are therefore the focus of this review: How can tissue-specific disorders result from alterations in global processes? Could ribosome specialization account for this difference?

Experimental Amyloidosis Induced by Immune Complex

1971 ◽  
Vol 29 ◽  
pp. 582-583
Author(s):  
A. Kawaoi
Keyword(s):  
Immune Complex ◽  
Systemic Amyloidosis ◽  
Human Diseases ◽  
Experimental Amyloidosis ◽  
Freund’S Complete Adjuvant ◽  
Freund's Complete Adjuvant ◽  
Immunological Approach ◽  
Experimentally Induced

Numbers of immunological approach have been made to the amyloidosis through the variety of predisposing human diseases and the experimentally induced animals by the greater number of agents. The results suggest an important role of impaired immunity involving both humoral and cell-mediated aspects.Recently the author has succeeded in producing amyloidosis in the rabbits and mice by the injections of immune complex of heat denatured DNA.The aim of this report is to demonstrate the details of the ultrastructure of the amyloidosis induced by heterologous insoluble immune complex. Eleven of twelve mice, dd strain, subcutaneously injected twice a week with Freund's complete adjuvant and four of seven animals intraperitonially injected developed systemic amyloidosis two months later from the initial injections. The spleens were electron microscopically observed.

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