scholarly journals The Neuromelanin Paradox and Its Dual Role in Oxidative Stress and Neurodegeneration

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 124
Author(s):  
Alexandra Moreno-García ◽  
Alejandra Kun ◽  
Miguel Calero ◽  
Olga Calero
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Neurodegenerative Disorders ◽  
Normal Aging ◽  
Saturation State ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Extracellular Release ◽  
Cellular Components

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, xenobiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and neurodegeneration related to its capabilities as an antioxidant and scavenging of harmful molecules, versus its involvement in oxidative stress and aberrant immune response, depending on NM saturation state and its extracellular release.

scholarly journals The Neuromelanin Paradox and its Dual Role in Oxidative Stress and Neurodegeneration

2020 ◽  
Author(s):  
Alexandra Moreno García ◽  
Alejandra Kun ◽  
Miguel Calero Lara ◽  
Olga Calero
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Neurodegenerative Disorders ◽  
Normal Aging ◽  
Saturation State ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Extracellular Release ◽  
Cellular Components

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, antibiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and catecholaminergic metabolism due to its capability as a pro-oxidant and other harmful molecules, versus its involvement in oxidative stress and aberrant immune response, which it is highly dependent on NM saturation state and its extracellular release.

scholarly journals Cytoplasmic mislocalization and mitochondrial colocalization of TDP-43 are common features between normal aged and young mice

2020 ◽  
Vol 245 (17) ◽  
pp. 1584-1593 ◽  
Author(s):  
Pichet Termsarasab ◽  
Thananan Thammongkolchai ◽  
Ju Gao ◽  
Luwen Wang ◽  
Jingjing Liang ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Neuronal Loss ◽  
Critical Factor ◽  
Brain Regions ◽  
Normal Aging ◽  
Age Related ◽  
Wide Range ◽  
Cytoplasmic Accumulation ◽  
Young Mice

Transactive response DNA binding protein 43 (TDP-43) pathologies have been well recognized in various neurodegenerative disorders including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). However, there have been limited studies on whether there are any TDP-43 alterations in normal aging. We investigated TDP-43 distribution in different brain regions in normal aged ( n =  3 for 26- or 36-month-old) compared to young ( n =  3 for 6- or 12-month-old) mice. In both normal aged and young mice, TDP-43 and phosphorylated TDP-43 (pTDP-43) demonstrated a unique pattern of distribution in neurons in some specific brain regions including the pontine nuclei, thalamus, CA3 region of the hippocampus, and orbital cortex. This pattern was demonstrated on higher magnification of high-resolution double fluorescence images and confocal microscopy as mislocalization of TDP-43 and pTDP-43, characterized by neuronal nuclear depletion and cytoplasmic accumulation in these brain regions, as well as colocalization between TDP-43 or pTDP-43 and mitochondria, similar to what has been described previously in neurodegenerative disorders. All these findings were identical in both normal aged and young mice. In summary, TDP-43 and pTDP-43 mislocalization from nucleus to cytoplasm and their colocalization with mitochondria in the specific brain regions are present not only in aging, but also in young healthy states. Our findings provide a new insight for the role of TDP-43 proteinopathy in health and diseases, and that aging may not be a critical factor for the development of TDP-43 proteinopathy in subpopulations of neurons. Impact statement Despite increasing evidence implicating the important role of TDP-43 in the pathogenesis of a wide range of age-related neurodegenerative diseases, there is limited study of TDP-43 proteinopathy and its association with mitochondria during normal aging. Our findings of cytoplasmic accumulation of TDP-43 that is highly colocalized with mitochondria in neurons in selective brain regions in young animals in the absence of neuronal loss provide a novel insight into the development of TDP-43 proteinopathy and its contribution to neuronal loss.

scholarly journals It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Antonella Tramutola ◽  
Fabio Di Domenico ◽  
Eugenio Barone ◽  
Marzia Perluigi ◽  
D. Allan Butterfield
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Ubiquitin Proteasome System ◽  
Oxidative Modification ◽  
Age Related ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
And Function ◽  
Cellular Components

Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

scholarly journals Unveiling the Role of Inflammation and Oxidative Stress on Age-Related Cardiovascular Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-20 ◽  
Author(s):  
Arthur José Pontes Oliveira de Almeida ◽  
Mathania Silva de Almeida Rezende ◽  
Sabine Helena Dantas ◽  
Sonaly de Lima Silva ◽  
Júlio César Pinheiro Lúcio de Oliveira ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Diseases ◽  
Inflammatory Process ◽  
Cell Damage ◽  
Stressful Environment ◽  
Age Related ◽  
Cellular Components ◽  
Global Population ◽  
And Oxidative Stress

The global population above 60 years has been growing exponentially in the last decades, which is accompanied by an increase in the prevalence of age-related chronic diseases, highlighting cardiovascular diseases (CVDs), such as hypertension, atherosclerosis, and heart failure. Aging is the main risk factor for these diseases. Such susceptibility to disease is explained, at least in part, by the increase of oxidative stress, in which it damages cellular components such as proteins, DNA, and lipids. In addition, the chronic inflammatory process in aging “inflammaging” also contributes to cell damage, creating a stressful environment which drives to the development of CVDs. Taken together, it is possible to identify the molecular connection between oxidative stress and the inflammatory process, especially by the crosstalk between the transcription factors Nrf-2 and NF-κB which are mediated by redox signalling and are involved in aging. Therapies that control this process are key targets in the prevention/combat of age-related CVDs. In this review, we show the basics of inflammation and oxidative stress, including the crosstalk between them, and the implications on age-related CVDs.

scholarly journals Benefits under the Sea: The Role of Marine Compounds in Neurodegenerative Disorders

Marine Drugs ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. 24
Author(s):  
Mariano Catanesi ◽  
Giulia Caioni ◽  
Vanessa Castelli ◽  
Elisabetta Benedetti ◽  
Michele d’Angelo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disorders ◽  
Extreme Temperature ◽  
Bioactive Molecules ◽  
Neuroprotective Effects ◽  
Physical Conditions ◽  
Adjuvant Therapies ◽  
Marine Habitats ◽  
Marine Compounds

Marine habitats offer a rich reservoir of new bioactive compounds with great pharmaceutical potential; the variety of these molecules is unique, and its production is favored by the chemical and physical conditions of the sea. It is known that marine organisms can synthesize bioactive molecules to survive from atypical environmental conditions, such as oxidative stress, photodynamic damage, and extreme temperature. Recent evidence proposed a beneficial role of these compounds for human health. In particular, xanthines, bryostatin, and 11-dehydrosinulariolide displayed encouraging neuroprotective effects in neurodegenerative disorders. This review will focus on the most promising marine drugs’ neuroprotective potential for neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. We will describe these marine compounds’ potential as adjuvant therapies for neurodegenerative diseases, based on their antioxidant, anti-inflammatory, and anti-apoptotic properties.

scholarly journals FHL-1 interacts with human RPE cells through the α5β1 integrin and confers protection against oxidative stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rawshan Choudhury ◽  
Nadhim Bayatti ◽  
Richard Scharff ◽  
Ewa Szula ◽  
Viranga Tilakaratna ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Fate ◽  
Retinal Pigment ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Rpe Cells ◽  
Age Related

AbstractRetinal pigment epithelial (RPE) cells that underlie the neurosensory retina are essential for the maintenance of photoreceptor cells and hence vision. Interactions between the RPE and their basement membrane, i.e. the inner layer of Bruch’s membrane, are essential for RPE cell health and function, but the signals induced by Bruch’s membrane engagement, and their contributions to RPE cell fate determination remain poorly defined. Here, we studied the functional role of the soluble complement regulator and component of Bruch’s membrane, Factor H-like protein 1 (FHL-1). Human primary RPE cells adhered to FHL-1 in a manner that was eliminated by either mutagenesis of the integrin-binding RGD motif in FHL-1 or by using competing antibodies directed against the α5 and β1 integrin subunits. These short-term experiments reveal an immediate protein-integrin interaction that were obtained from primary RPE cells and replicated using the hTERT-RPE1 cell line. Separate, longer term experiments utilising RNAseq analysis of hTERT-RPE1 cells bound to FHL-1, showed an increased expression of the heat-shock protein genes HSPA6, CRYAB, HSPA1A and HSPA1B when compared to cells bound to fibronectin (FN) or laminin (LA). Pathway analysis implicated changes in EIF2 signalling, the unfolded protein response, and mineralocorticoid receptor signalling as putative pathways. Subsequent cell survival assays using H2O2 to induce oxidative stress-induced cell death suggest hTERT-RPE1 cells had significantly greater protection when bound to FHL-1 or LA compared to plastic or FN. These data show a non-canonical role of FHL-1 in protecting RPE cells against oxidative stress and identifies a novel interaction that has implications for ocular diseases such as age-related macular degeneration.

scholarly journals Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels

2021 ◽  
Vol 22 (3) ◽  
pp. 1296
Author(s):  
Yue Ruan ◽  
Subao Jiang ◽  
Adrian Gericke
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Therapeutic Strategies ◽  
Vision Impairment ◽  
Age Related Macular Degeneration ◽  
Oxygen Species ◽  
Age Related

Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.

scholarly journals The Protective Role of Sestrin2 in Atherosclerotic and Cardiac Diseases

2021 ◽  
Vol 22 (3) ◽  
pp. 1200
Author(s):  
Yoshimi Kishimoto ◽  
Kazuo Kondo ◽  
Yukihiko Momiyama
Keyword(s):  
Oxidative Stress ◽  
Protective Role ◽  
Chronic Inflammatory Disease ◽  
Atherosclerotic Disease ◽  
Cardiac Diseases ◽  
Compensatory Response ◽  
Age Related ◽  
Anti Oxidant ◽  
Progression Of Atherosclerosis

Atherosclerotic disease, such as coronary artery disease (CAD), is known to be a chronic inflammatory disease, as well as an age-related disease. Excessive oxidative stress produced by reactive oxygen species (ROS) contributes to the pathogenesis of atherosclerosis. Sestrin2 is an anti-oxidant protein that is induced by various stresses such as hypoxia, DNA damage, and oxidative stress. Sestrin2 is also suggested to be associated with aging. Sestrin2 is expressed and secreted mainly by macrophages, endothelial cells, and cardiomyocytes. Sestrin2 plays an important role in suppressing the production and accumulation of ROS, thus protecting cells from oxidative damage. Since sestrin2 is reported to have anti-oxidant and anti-inflammatory properties, it may play a protective role against the progression of atherosclerosis and may be a potential therapeutic target for the amelioration of atherosclerosis. Regarding the association between blood sestrin2 levels and atherosclerotic disease, the blood sestrin2 levels in patients with CAD or carotid atherosclerosis were reported to be high. High blood sestrin2 levels in patients with such atherosclerotic disease may reflect a compensatory response to increased oxidative stress and may help protect against the progression of atherosclerosis. This review describes the protective role of sestrin2 against the progression of atherosclerotic and cardiac diseases.

scholarly journals The role of balanced supplementation in diet of age-related macular degeneration patients

2021 ◽  
Vol 8 (1) ◽  
pp. 19-25
Author(s):  
Iwona Kusz vel Sobczuk ◽  
Anna Święch
Keyword(s):  
Vitamin D ◽  
Immune Response ◽  
Macular Degeneration ◽  
Vitamin B6 ◽  
Age Related Macular Degeneration ◽  
Response Modulation ◽  
Omega 3 ◽  
Age Related ◽  
Immune Response Modulation

Aim: The aim of the article was to discuss the role of balanced supplementation in diet of age-related macular degeneration patients. Methods: This review was carried out using comprehensive and systematic literature reports on the role of supplementation of vitamin D, vitamin C, vitamin E, vitamin B6, vitamin B12, zinc, lutein, zeaxanthin, omega-3 acid and folic acid in the prevention of AMD. Results: Vitamins, minerals and carotenoids are essential for the proper retinal function over an inflammation and immune response modulation. Conclusions: Vitamins, minerals and carotenoids discussed in the article have anti-inflammatory and antioxidative properties in the management of AMD progression. Accordingly, it is relevant to assure the appropriate level of these nutrients in a diet of AMD patients.

scholarly journals The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

2021 ◽  
Vol 13 ◽  
Author(s):  
Nicolás W. Martinez ◽  
Felipe E. Gómez ◽  
Soledad Matus
Keyword(s):  
Protein Kinase ◽  
Pathological Process ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Kinase R ◽  
Eukaryotic Translation ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Initiation Factor 2

There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer’s disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR’s contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

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