With or Without You: Co-chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

2021 ◽  
Author(s):  
Selin Altinok ◽  
Rebekah Sanchez-Hodge ◽  
Mariah Stewart ◽  
Kaitlan Smith ◽  
Jonathan C. Schisler
Keyword(s):  
Protein Quality ◽  
Cellular Stress Response ◽  
Therapeutic Approaches ◽  
Post Translational Modifications ◽  
Chaperone Function ◽  
Recent Developments ◽  
The Face ◽  
Health And Disease ◽  
Shock Proteins ◽  
Triage Decisions

Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintaining protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensuring cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, focusing on cardioprotection, neuroprotection, and cancer. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

scholarly journals With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3121
Author(s):  
Selin Altinok ◽  
Rebekah Sanchez-Hodge ◽  
Mariah Stewart ◽  
Kaitlan Smith ◽  
Jonathan C. Schisler
Keyword(s):  
Protein Quality ◽  
Cellular Stress Response ◽  
Therapeutic Approaches ◽  
Post Translational Modifications ◽  
Chaperone Function ◽  
Recent Developments ◽  
The Face ◽  
Health And Disease ◽  
Shock Proteins ◽  
Triage Decisions

Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

scholarly journals Impaired Autophagy in Motor Neurons: A Final Common Mechanism of Injury and Death

Physiology ◽  
2018 ◽  
Vol 33 (3) ◽  
pp. 211-224 ◽  
Author(s):  
Maria A. Gonzalez Porras ◽  
Gary C. Sieck ◽  
Carlos B. Mantilla
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Common Mechanism ◽  
Mechanism Of Injury ◽  
Therapeutic Approaches ◽  
Motor Neuron Diseases ◽  
Digestion Process ◽  
Cord Injury ◽  
Recent Developments ◽  
Health And Disease

Autophagy is a cellular digestion process that contributes to cellular homeostasis and adaptation by the elimination of proteins and damaged organelles. Evidence suggests that dysregulation of autophagy plays a role in neurodegenerative diseases, including motor neuron disorders. Herein, we review emerging evidence indicating the roles of autophagy in physiological motor neuron processes and its function in specific compartments. Moreover, we discuss the involvement of autophagy in the pathogenesis of motor neuron diseases, including spinal cord injury and aging, and recent developments that offer promising therapeutic approaches to mitigate effects of dysregulated autophagy in health and disease.

scholarly journals The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity

2022 ◽  
Author(s):  
Calum C. Bain ◽  
Andrew S. MacDonald
Keyword(s):  
New Technologies ◽  
Model Systems ◽  
Lung Macrophage ◽  
Renaissance Period ◽  
Recent Developments ◽  
The Face ◽  
Health And Disease ◽  
And Function ◽  
The Impact ◽  
Novel Model

AbstractThe last decade has been somewhat of a renaissance period for the field of macrophage biology. This renewed interest, combined with the advent of new technologies and development of novel model systems to assess different facets of macrophage biology, has led to major advances in our understanding of the diverse roles macrophages play in health, inflammation, infection and repair, and the dominance of tissue environments in influencing all of these areas. Here, we discuss recent developments in our understanding of lung macrophage heterogeneity, ontogeny, metabolism and function in the context of health and disease, and highlight core conceptual advances and key unanswered questions that we believe should be focus of work in the coming years.

Neurochemistry of L-Glutamate Transport in the CNS: A Review of Thirty Years of Progress

2001 ◽  
Vol 66 (9) ◽  
pp. 1315-1340 ◽  
Author(s):  
Vladimir J. Balcar ◽  
Akiko Takamoto ◽  
Yukio Yoneda
Keyword(s):  
Molecular Biology ◽  
Glutamate Transport ◽  
Mammalian Brain ◽  
Activity Data ◽  
System A ◽  
Recent Developments ◽  
The Central Nervous System ◽  
Health And Disease ◽  
Disease Analysis

The review highlights the landmark studies leading from the discovery and initial characterization of the Na+-dependent "high affinity" uptake in the mammalian brain to the cloning of individual transporters and the subsequent expansion of the field into the realm of molecular biology. When the data and hypotheses from 1970's are confronted with the recent developments in the field, we can conclude that the suggestions made nearly thirty years ago were essentially correct: the uptake, mediated by an active transport into neurons and glial cells, serves to control the extracellular concentrations of L-glutamate and prevents the neurotoxicity. The modern techniques of molecular biology may have provided additional data on the nature and location of the transporters but the classical neurochemical approach, using structural analogues of glutamate designed as specific inhibitors or substrates for glutamate transport, has been crucial for the investigations of particular roles that glutamate transport might play in health and disease. Analysis of recent structure/activity data presented in this review has yielded a novel insight into the pharmacological characteristics of L-glutamate transport, suggesting existence of additional heterogeneity in the system, beyond that so far discovered by molecular genetics. More compounds that specifically interact with individual glutamate transporters are urgently needed for more detailed investigations of neurochemical characteristics of glutamatergic transport and its integration into the glutamatergic synapses in the central nervous system. A review with 162 references.

scholarly journals Implementing the Proclamation of Stroke and Potentially Preventable Dementias

2018 ◽  
Vol 13 (8) ◽  
pp. 780-786 ◽  
Author(s):  
Vladimir Hachinski ◽  
Detlev Ganten ◽  
Daniel Lackland ◽  
Reinhold Kreutz ◽  
Konstantinos Tsioufis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Alzheimer Disease ◽  
Large Population ◽  
Therapeutic Approaches ◽  
Brain Health ◽  
Vascular Dysregulation ◽  
New Therapeutic Approaches ◽  
The World ◽  
National Organizations ◽  
Recent Developments

Brain health plays a central role in wellbeing and in the management of chronic diseases. Stroke and dementia pose the two greatest threats to brain health, but recent developments suggest the possibility that preventing stroke may also prevent some dementias: 1. A large population study showed a 32% decrease in the incidence of stroke and a concomitant 7% reduction in the incidence of dementia; 2. Treatment of atrial fibrillation resulted not only in stroke reduction, but a 48% decrease in dementia; 3. A hypothesis free analyses has shown that the first phase of Alzheimer disease involves vascular dysregulation, opening the door to new therapeutic approaches; 4. Cognitive impairment, often treatable and reversible, accompanies heart and kidney failure. These developments, combined with the knowledge that stroke, dementia and heart disease share the same major treatable risk factors, particularly hypertension, offers an opportunity for their joint prevention. This aspiration is expressed by a Proclamation of the World Stroke Organization on Stroke and Potentially Preventable Dementias and endorsed by the World Heart Federation, the World Hypertension League, Alzheimer Disease International and 18 other international, regional and national organizations as a call for action.

scholarly journals Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2798 ◽  
Author(s):  
Thanh Hung Nguyen ◽  
Frederic G. Barr
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Young Adults ◽  
Soft Tissue ◽  
Chromosomal Translocation ◽  
Murine Models ◽  
Therapeutic Approaches ◽  
Recent Developments ◽  
Children And Young Adults ◽  
Oncogenic Transcription Factor

Rhabdomyosarcoma (RMS) is a family of soft tissue cancers that are related to the skeletal muscle lineage and predominantly occur in children and young adults. A specific chromosomal translocation t(2;13)(q35;q14) that gives rise to the chimeric oncogenic transcription factor PAX3-FOXO1 has been identified as a hallmark of the aggressive alveolar subtype of RMS. PAX3-FOXO1 cooperates with additional molecular changes to promote oncogenic transformation and tumorigenesis in various human and murine models. Its expression is generally restricted to RMS tumor cells, thus providing a very specific target for therapeutic approaches for these RMS tumors. In this article, we review the recent understanding of PAX3-FOXO1 as a transcription factor in the pathogenesis of this cancer and discuss recent developments to target this oncoprotein for treatment of RMS.

scholarly journals Effects of modifications of α-crystallin on its chaperone and other properties

2002 ◽  
Vol 364 (3) ◽  
pp. 711-717 ◽  
Author(s):  
Barry K. DERHAM ◽  
John J. HARDING
Keyword(s):  
Congenital Cataract ◽  
Point Mutations ◽  
Small Heat Shock Protein ◽  
High Molecular Mass ◽  
Lens Crystallins ◽  
Post Translational Modifications ◽  
Chaperone Function ◽  
Arginine Residues

The role of α-crystallin, a small heat-shock protein and chaperone, may explain how the lens stays transparent for so long. α-Crystallin prevents the aggregation of other lens crystallins and proteins that have become unfolded by ‘trapping’ the protein in a high-molecular-mass complex. However, during aging, the chaperone function of α-crystallin becomes compromised, allowing the formation of light-scattering aggregates that can proceed to form cataracts. Within the central part of the lens there is no turnover of damaged protein, and therefore post-translational modifications of α-crystallin accumulate that can reduce chaperone function; this is compounded in cataract lenses. Extensive in vitro glycation, carbamylation and oxidation all decrease chaperone ability. In the present study, we report the effect of the modifiers malondialdehyde, acetaldehyde and methylglyoxal, all of which are pertinent to cataract. Also modification by aspirin, which is known to delay cataract and other diseases, has been investigated. Recently, two point mutations of arginine residues were shown to cause congenital cataract. 1,2-Cyclohexanedione modifies arginine residues, and the extent of modification needed for a change in chaperone function was investigated. Only methylglyoxal and extensive modification by 1,2-cyclohexanedione caused a decrease in chaperone function. This highlights the robust nature of α-crystallin.

scholarly journals Emerging mass spectrometry-based proteomics methodologies for novel biomedical applications

2020 ◽  
Vol 48 (5) ◽  
pp. 1953-1966
Author(s):  
Lindsay K. Pino ◽  
Jacob Rose ◽  
Amy O'Broin ◽  
Samah Shah ◽  
Birgit Schilling
Keyword(s):  
Mass Spectrometry ◽  
Human Health ◽  
Protein Complexes ◽  
Protein Quantification ◽  
Intact Protein ◽  
Protein Signaling ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Health And Disease ◽  
Proteomics Research

Research into the basic biology of human health and disease, as well as translational human research and clinical applications, all benefit from the growing accessibility and versatility of mass spectrometry (MS)-based proteomics. Although once limited in throughput and sensitivity, proteomic studies have quickly grown in scope and scale over the last decade due to significant advances in instrumentation, computational approaches, and bio-sample preparation. Here, we review these latest developments in MS and highlight how these techniques are used to study the mechanisms, diagnosis, and treatment of human diseases. We first describe recent groundbreaking technological advancements for MS-based proteomics, including novel data acquisition techniques and protein quantification approaches. Next, we describe innovations that enable the unprecedented depth of coverage in protein signaling and spatiotemporal protein distributions, including studies of post-translational modifications, protein turnover, and single-cell proteomics. Finally, we explore new workflows to investigate protein complexes and structures, and we present new approaches for protein–protein interaction studies and intact protein or top-down MS. While these approaches are only recently incipient, we anticipate that their use in biomedical MS proteomics research will offer actionable discoveries for the improvement of human health.

scholarly journals Morphological Alterations and Stress Protein Variations in Lung Biopsies Obtained from Autopsies of COVID-19 Subjects

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3136
Author(s):  
Rosario Barone ◽  
Antonella Marino Gammazza ◽  
Letizia Paladino ◽  
Alessandro Pitruzzella ◽  
Giulio Spinoso ◽  
...  
Keyword(s):  
Molecular Chaperones ◽  
Histological Analysis ◽  
Stress Protein ◽  
Control Group ◽  
Post Translational Modifications ◽  
Morphological Alterations ◽  
New Biomarkers ◽  
Lung Biopsies ◽  
Cell Stress Response ◽  
Shock Proteins

Molecular chaperones, many of which are heat shock proteins, play a role in cell stress response and regulate the immune system in various ways, such as in inflammatory/autoimmune reactions. It would be interesting to study the involvement of these molecules in the damage done to COVID-19-infected lungs. In our study, we performed a histological analysis and an immunomorphological evaluation on lung samples from subjects who succumbed to COVID-19 and subjects who died from other causes. We also assessed Hsp60 and Hsp90 distribution in lung samples to determine their location and post-translational modifications. We found histological alterations that could be considered pathognomonic for COVID-19-related lung disease. Hsp60 and Hsp90 immunopositivity was significantly higher in the COVID-19 group compared to the controls, and immunolocalization was in the plasma membrane of the endothelial cells in COVID-19 subjects. The colocalization ratios for Hsp60/3-nitrotyrosine and Hsp60/acetylate-lisine were significantly increased in the COVID-19 group compared to the control group, similar to the colocalization ratio for Hsp90/acetylate-lisine. The histological and immunohistochemical findings led us to hypothesize that Hsp60 and Hsp90 might have a role in the onset of the thromboembolic phenomena that lead to death in a limited number of subjects affected by COVID-19. Further studies on a larger number of samples obtained from autopsies would allow to confirm these data as well as discover new biomarkers useful in the battle against this disease.

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