scholarly journals Natural Products as Modulators of the Proteostasis Machinery: Implications in Neurodegenerative Diseases

2019 ◽  
Vol 20 (19) ◽  
pp. 4666 ◽  
Author(s):  
Karina Cuanalo-Contreras ◽  
Ines Moreno-Gonzalez
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Protein Quality ◽  
Biological Function ◽  
Current Knowledge ◽  
Three Dimensional ◽  
Protein Homeostasis ◽  
Primary Role ◽  
Damage Protein

Proteins play crucial and diverse roles within the cell. To exert their biological function they must fold to acquire an appropriate three-dimensional conformation. Once their function is fulfilled, they need to be properly degraded to hamper any possible damage. Protein homeostasis or proteostasis comprises a complex interconnected network that regulates different steps of the protein quality control, from synthesis and folding, to degradation. Due to the primary role of proteins in cellular function, the integrity of this network is critical to assure functionality and health across lifespan. Proteostasis failure has been reported in the context of aging and neurodegeneration, such as Alzheimer’s and Parkinson’s disease. Therefore, targeting the proteostasis elements emerges as a promising neuroprotective therapeutic approach to prevent or ameliorate the progression of these disorders. A variety of natural products are known to be neuroprotective by protein homeostasis interaction. In this review, we will focus on the current knowledge regarding the use of natural products as modulators of different components of the proteostasis machinery within the framework of age-associated neurodegenerative diseases.

scholarly journals DNAJ Proteins in neurodegeneration: essential and protective factors

2017 ◽  
Vol 373 (1738) ◽  
pp. 20160534 ◽  
Author(s):  
Christina Zarouchlioti ◽  
David A. Parfitt ◽  
Wenwen Li ◽  
Lauren M. Gittings ◽  
Michael E. Cheetham
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Conformational Changes ◽  
Molecular Chaperones ◽  
Protein Quality ◽  
Misfolded Proteins ◽  
Protein Homeostasis ◽  
Polyglutamine Expansion ◽  
Binding Domains

Maintenance of protein homeostasis is vitally important in post-mitotic cells, particularly neurons. Neurodegenerative diseases such as polyglutamine expansion disorders—like Huntington's disease or spinocerebellar ataxia (SCA), Alzheimer's disease, fronto-temporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease—are often characterized by the presence of inclusions of aggregated protein. Neurons contain complex protein networks dedicated to protein quality control and maintaining protein homeostasis, or proteostasis. Molecular chaperones are a class of proteins with prominent roles in maintaining proteostasis, which act to bind and shield hydrophobic regions of nascent or misfolded proteins while allowing correct folding, conformational changes and enabling quality control. There are many different families of molecular chaperones with multiple functions in proteostasis. The DNAJ family of molecular chaperones is the largest chaperone family and is defined by the J-domain, which regulates the function of HSP70 chaperones. DNAJ proteins can also have multiple other protein domains such as ubiquitin-interacting motifs or clathrin-binding domains leading to diverse and specific roles in the cell, including targeting client proteins for degradation via the proteasome, chaperone-mediated autophagy and uncoating clathrin-coated vesicles. DNAJ proteins can also contain ER-signal peptides or mitochondrial leader sequences, targeting them to specific organelles in the cell. In this review, we discuss the multiple roles of DNAJ proteins and in particular focus on the role of DNAJ proteins in protecting against neurodegenerative diseases caused by misfolded proteins. We also discuss the role of DNAJ proteins as direct causes of inherited neurodegeneration via mutations in DNAJ family genes. This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.

scholarly journals The Heart of the Alzheimer's: A Mindful View of Heart Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Alessandro Evangelisti ◽  
Helen Butler ◽  
Federica del Monte
Keyword(s):  
Heart Disease ◽  
Cardiovascular Diseases ◽  
Cellular Response ◽  
Protein Quality ◽  
Current Knowledge ◽  
Current Evidence ◽  
Protein Accumulation ◽  
Primary Role ◽  
The Brain

Purpose of Review: This review summarizes the current evidence for the involvement of proteotoxicity and protein quality control systems defects in diseases of the central nervous and cardiovascular systems. Specifically, it presents the commonalities between the pathophysiology of protein misfolding diseases in the heart and the brain.Recent Findings: The involvement of protein homeostasis dysfunction has been for long time investigated and accepted as one of the leading pathophysiological causes of neurodegenerative diseases. In cardiovascular diseases instead the mechanistic focus had been on the primary role of Ca2+ dishomeostasis, myofilament dysfunction as well as extracellular fibrosis, whereas no attention was given to misfolding of proteins as a pathogenetic mechanism. Instead, in the recent years, several contributions have shown protein aggregates in failing hearts similar to the ones found in the brain and increasing evidence have highlighted the crucial importance that proteotoxicity exerts via pre-amyloidogenic species in cardiovascular diseases as well as the prominent role of the cellular response to misfolded protein accumulation. As a result, proteotoxicity, unfolding protein response (UPR), and ubiquitin-proteasome system (UPS) have recently been investigated as potential key pathogenic pathways and therapeutic targets for heart disease.Summary: Overall, the current knowledge summarized in this review describes how the misfolding process in the brain parallels in the heart. Understanding the folding and unfolding mechanisms involved early through studies in the heart will provide new knowledge for neurodegenerative proteinopathies and may prepare the stage for targeted and personalized interventions.

scholarly journals Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Immuno ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 78-90
Author(s):  
Johannes Burtscher ◽  
Grégoire P. Millet
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Cell Types ◽  
Brain Cell ◽  
Special Focus ◽  
Molecular Alterations ◽  
Research Fields

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

scholarly journals Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases

2017 ◽  
Vol 216 (12) ◽  
pp. 3917-3929 ◽  
Author(s):  
Hibiki Kawamata ◽  
Giovanni Manfredi
Keyword(s):  
Nervous System ◽  
Oxidative Phosphorylation ◽  
Neurodegenerative Diseases ◽  
Gene Mutations ◽  
Misfolded Proteins ◽  
Protein Homeostasis ◽  
Abnormal Protein ◽  
Oxidative Phosphorylation System ◽  
Intermediate Metabolism

Mitochondria participate in essential processes in the nervous system such as energy and intermediate metabolism, calcium homeostasis, and apoptosis. Major neurodegenerative diseases are characterized pathologically by accumulation of misfolded proteins as a result of gene mutations or abnormal protein homeostasis. Misfolded proteins associate with mitochondria, forming oligomeric and fibrillary aggregates. As mitochondrial dysfunction, particularly of the oxidative phosphorylation system (OXPHOS), occurs in neurodegeneration, it is postulated that such defects are caused by the accumulation of misfolded proteins. However, this hypothesis and the pathological role of proteinopathies in mitochondria remain elusive. In this study, we critically review the proposed mechanisms whereby exemplary misfolded proteins associate with mitochondria and their consequences on OXPHOS.

scholarly journals Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

2020 ◽  
Vol 21 (22) ◽  
pp. 8767
Author(s):  
Nicole Jacqueline Jensen ◽  
Helena Zander Wodschow ◽  
Malin Nilsson ◽  
Jørgen Rungby
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Brain Metabolism ◽  
Ketone Bodies ◽  
Current Knowledge ◽  
Ketogenic Diets ◽  
Cognitive Benefits ◽  
The Brain

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

scholarly journals On the Role of sIL-2R Measurements in Rheumatoid Arthritis and Cancers

2005 ◽  
Vol 2005 (3) ◽  
pp. 121-130 ◽  
Author(s):  
Anna Maria Witkowska
Keyword(s):  
Rheumatoid Arthritis ◽  
Cancer Cells ◽  
T Lymphocyte ◽  
Biological Function ◽  
Current Knowledge ◽  
Lymphocyte Activation ◽  
Soluble Receptor ◽  
Disease Progress ◽  
Lines Of Evidence

A soluble IL-2 receptor (sIL-2R) is a circulating form of a membrane receptor localized on lymphoid and some cancer cells. The biological function of sIL-2R has not been completely understood. Substantially, it seems to reflect T-lymphocyte activation in diseases of different pathology. Moreover, the soluble receptor has been considered, at least in part, responsible for unsuccessful immunotherapy with IL-2 in cancers. Several lines of evidence indicate sIL-2R measurements to be useful in determining disease progress and prognosis. This review summarizes current knowledge on the sIL-2R behavior in RA and solid cancers of varied etiology.

scholarly journals Completely engaged three-dimensional mandibular gear-like structures in the adult horned beetles: reconsideration of bark-carving behaviors (Coleoptera, Scarabaeidae, Dynastinae)

ZooKeys ◽  
2019 ◽  
Vol 813 ◽  
pp. 89-110 ◽  
Author(s):  
Wataru Ichiishi ◽  
Shinpei Shimada ◽  
Takashi Motobayashi ◽  
Hiroaki Abe
Keyword(s):  
Three Dimensional ◽  
Surface Structures ◽  
The Other ◽  
Primary Role ◽  
Beetle Species ◽  
Tree Sap ◽  
Horned Beetle ◽  
Horned Beetles

Adult horned beetles (Coleoptera, Scarabaeidae, Dynastinae) such as Trypoxylusdichotomus (Linnaeus, 1771) exhibit bark-carving behaviors to feed on tree sap, in part by using small projections of the clypeus. However, in the present experiments, adult horned beetles (T.dichotomus and Dynasteshercules (Linnaeus, 1758)) used their mandibles and not the projections of the clypeus to carve bark. Our findings show the presence of completely engaged mandibular interlocking, gear-like surface structures in molar areas that guide mandible opening and closure, and lead to completely synchronous movements of adult horned beetle mandibles. Three-dimensional shapes of these mandibular gear-like structures are complex and remained in contact after the death of a beetle. Moreover, adult horned beetles often performed bark-carving behaviors using only the mandible of one side, suggesting that the primary role of the mandibular gear-like structure is to prevent breakage of the mandible by transmitting load from one mandible to the other. Among the 22 Dynastinae and 16 other beetle species examined (not Dynastinae), the gear-like structure was found in all the Dynastinae species and in no other species.

scholarly journals Mitochondria and Aging—The Role of Exercise as a Countermeasure

Biology ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 40 ◽  
Author(s):  
Mats I Nilsson ◽  
Mark A Tarnopolsky
Keyword(s):  
Reactive Oxygen Species Generation ◽  
Biological Aging ◽  
Primary Role ◽  
Oxygen Species ◽  
Vicious Cycle ◽  
Life And Death ◽  
Cell Functions ◽  
Age Related ◽  
Damage Protein

Mitochondria orchestrate the life and death of most eukaryotic cells by virtue of their ability to supply adenosine triphosphate from aerobic respiration for growth, development, and maintenance of the ‘physiologic reserve’. Although their double-membrane structure and primary role as ‘powerhouses of the cell’ have essentially remained the same for ~2 billion years, they have evolved to regulate other cell functions that contribute to the aging process, such as reactive oxygen species generation, inflammation, senescence, and apoptosis. Biological aging is characterized by buildup of intracellular debris (e.g., oxidative damage, protein aggregates, and lipofuscin), which fuels a ‘vicious cycle’ of cell/DNA danger response activation (CDR and DDR, respectively), chronic inflammation (‘inflammaging’), and progressive cell deterioration. Therapeutic options that coordinately mitigate age-related declines in mitochondria and organelles involved in quality control, repair, and recycling are therefore highly desirable. Rejuvenation by exercise is a non-pharmacological approach that targets all the major hallmarks of aging and extends both health- and lifespan in modern humans.

scholarly journals Role of Antioxidants in Alleviating Bisphenol A Toxicity

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1105
Author(s):  
Shehreen Amjad ◽  
Md Saidur Rahman ◽  
Myung-Geol Pang
Keyword(s):  
Bisphenol A ◽  
Biological Function ◽  
Current Knowledge ◽  
Biochemical Properties ◽  
Endocrine Function ◽  
Enzymatic Antioxidants ◽  
Oxidation Reactions ◽  
Food And Beverage ◽  
Cellular Oxidation

Bisphenol A (BPA) is an oestrogenic endocrine disruptor widely used in the production of certain plastics, e.g., polycarbonate, hard and clear plastics, and epoxy resins that act as protective coating for food and beverage cans. Human exposure to this chemical is thought to be ubiquitous. BPA alters endocrine function, thereby causing many diseases in human and animals. In the last few decades, studies exploring the mechanism of BPA activity revealed a direct link between BPA-induced oxidative stress and disease pathogenesis. Antioxidants, reducing agents that prevent cellular oxidation reactions, can protect BPA toxicity. Although the important role of antioxidants in minimizing BPA stress has been demonstrated in many studies, a clear consensus on the associated mechanisms is needed, as well as the directives on their efficacy and safety. Herein, considering the distinct biochemical properties of BPA and antioxidants, we provide a framework for understanding how antioxidants alleviate BPA-associated stress. We summarize the current knowledge on the biological function of enzymatic and non-enzymatic antioxidants, and discuss their practical potential as BPA-detoxifying agents.

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