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Mitochondrial dysfunction neurodegenerative disease

Duojiao Wu, Xiangdong Wang, Hongzhi Sun
Mitochondrial malfunction is related to aging and to the onset of many diseases, such as obesity/diabetes, cancer, and cardiovascular and neurodegenerative diseases. The molecular principles of biological and toxicological processes the mitochondria can regulate should be disease-specific, cell type-specific, and drug targetable. Mitochondrial biology and toxicology is evolving and undergoing a revolution through fast-developing biotechnologies garnering increasing attention due to the importance of targeted therapies...
March 6, 2018: Cell Biology and Toxicology
Ru-Yi Zhang, Lan Zhang, Li Zhang, Yu-Lan Wang, Lin Li
Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. Emerging evidence indicates that there is a tight relationship between mitochondrial dysfunction and β-amyloid (Aβ) formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on Aβ production and neurotrophins in the brains of rats by using a mitochondrial dysfunction rat model induced by sodium azide (NaN3 ), an inhibitor of mitochondrial cytochrome c oxidase (COX)...
March 5, 2018: Journal of Natural Medicines
N K Singhal, K Alkhayer, J Shelestak, R Clements, E Freeman, J McDonough
Multiple sclerosis (MS) is a neuro-inflammatory and demyelinating disease. Downregulation of neuronal mitochondrial gene expression and activity have been reported in several studies of MS. We have previously shown that hemoglobin-β (Hbb) signals to the nucleus of neurons and upregulates H3K4me3, a histone mark involved in regulating cellular metabolism and differentiation. The present study was undertaken to evaluate the effect of erythropoietin (EPO) on the upregulation of hemoglobin and mitochondrial-associated neuroprotection...
March 1, 2018: Molecular Neurobiology
Estela Area-Gomez, Ad de Groof, Eduardo Bonilla, Jorge Montesinos, Kurenai Tanji, Istvan Boldogh, Liza Pon, Eric A Schon
In the last few years, increased emphasis has been devoted to understanding the contribution of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) to human pathology in general, and neurodegenerative diseases in particular. A major reason for this is the central role that this subdomain of the ER plays in metabolic regulation and in mitochondrial biology. As such, aberrant MAM function may help explain the seemingly unrelated metabolic abnormalities often seen in neurodegeneration. In the specific case of Alzheimer disease (AD), besides perturbations in calcium and lipid homeostasis, there are numerous documented alterations in mitochondrial behavior and function, including reduced respiratory chain activity and oxidative phosphorylation, increased free radical production, and altered organellar morphology, dynamics, and positioning (especially perinuclear mitochondria)...
February 28, 2018: Cell Death & Disease
Nathalie Bernard-Marissal, Roman Chrast, Bernard L Schneider
Recent progress in the understanding of neurodegenerative diseases revealed that multiple molecular mechanisms contribute to pathological changes in neurons. A large fraction of these alterations can be linked to dysfunction in the endoplasmic reticulum (ER) and mitochondria, affecting metabolism and secretion of lipids and proteins, calcium homeostasis, and energy production. Remarkably, these organelles are interacting with each other at specialized domains on the ER called mitochondria-associated membranes (MAMs)...
February 28, 2018: Cell Death & Disease
Marija Sajic, Keila Kazue Ida, Ryan Canning, Norman A Gregson, Michael R Duchen, Kenneth J Smith
BACKGROUND: Small-diameter, myelinated axons are selectively susceptible to dysfunction in several inflammatory PNS and CNS diseases, resulting in pain and degeneration, but the mechanism is not known. METHODS: We used in vivo confocal microscopy to compare the effects of inflammation in experimental autoimmune neuritis (EAN), a model of Guillain-Barré syndrome (GBS), on mitochondrial function and transport in large- and small-diameter axons. We have compared mitochondrial function and transport in vivo in (i) healthy axons, (ii) axons affected by experimental autoimmune neuritis, and (iii) axons in which mitochondria were focally damaged by laser induced photo-toxicity...
February 27, 2018: Journal of Neuroinflammation
Su Eun Choi, Yun Sun Park, Hyun Chul Koh
Inflammation generated by environmental toxicants including pesticides could be one of the factors underlying neuronal cell damage in neurodegenerative diseases. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in PC12 cells treated with diquat. We found that diquat induced apoptosis, as demonstrated by the activation of caspases and nuclear condensation, inhibition of mitochondrial complex I activity, and decreased ATP level in PC12 cells. Diquat also reduced the dopamine level, indicating that cell death induced by diquat is due to cytotoxicity of dopaminergic neuronal components in these cells...
February 27, 2018: Environmental Toxicology
Devesh Tewari, Adrian M Stankiewicz, Andrei Mocan, Archana N Sah, Nikolay T Tzvetkov, Lukasz Huminiecki, Jarosław O Horbańczuk, Atanas G Atanasov
Dementia is a clinical syndrome wherein gradual decline of mental and cognitive capabilities of an afflicted person takes place. Dementia is associated with various risk factors and conditions such as insufficient cerebral blood supply, toxin exposure, mitochondrial dysfunction, oxidative damage, and often coexisting with some neurodegenerative disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Although there are well-established (semi-)synthetic drugs currently used for the management of AD and AD-associated dementia, most of them have several adverse effects...
2018: Frontiers in Aging Neuroscience
Claudia Marinangeli, Jérome Kluza, Philippe Marchetti, Luc Buée, Valérie Vingtdeux
AMP-activated protein kinase (AMPK) is the intracellular master energy sensor and metabolic regulator. AMPK is involved in cell energy homeostasis through the regulation of glycolytic flux and mitochondrial biogenesis. Interestingly, metabolic dysfunctions and AMPK deregulations are observed in many neurodegenerative diseases, including Alzheimer's. While these deregulations could play a key role in the development of these diseases, the study of metabolic fluxes has remained quite challenging and time-consuming...
2018: Methods in Molecular Biology
Gautam Pareek, Ruth E Thomas, Leo J Pallanck
The progressive accumulation of dysfunctional mitochondria is implicated in aging and in common diseases of the elderly. To oppose this occurrence, organisms employ a variety of strategies, including the selective degradation of oxidatively damaged and misfolded mitochondrial proteins. Genetic studies in yeast indicate that the ATPase Associated with diverse cellular Activities (AAA+ ) family of mitochondrial proteases account for a substantial fraction of this protein degradation, but their metazoan counterparts have been little studied, despite the fact that mutations in the genes encoding these proteases cause a variety of human diseases...
February 21, 2018: Cell Death & Disease
Maryem Bezine, Sonia Maatoug, Rym Ben Khalifa, Meryam Debbabi, Amira Zarrouk, Yuqin Wang, William J Griffiths, Thomas Nury, Mohammad Samadi, Anne Vejux, Jérôme de Sèze, Thibault Moreau, Riadh Kharrat, Mohamed El Ayeb, Gérard Lizard
Little is known about K+ regulation playing major roles in the propagation of nerve impulses, as well as in apoptosis and inflammasome activation involved in neurodegeneration. As increased levels of 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC) and tetracosanoic acid (C24:0) have been observed in patients with neurodegenerative diseases, we studied the effect of 24 and/or 48 h of treatment with 7KC, 24S-OHC and C24:0 on Kv3.1b potassium channel level, intracellular K+ concentration, oxidative stress, mitochondrial dysfunction, and plasma membrane permeability in 158N oligodendrocytes and BV-2 microglial cells...
February 17, 2018: Biochimie
Angela Trovato Salinaro, Manuela Pennisi, Rosanna Di Paola, Maria Scuto, Rosalia Crupi, Maria Teresa Cambria, Maria Laura Ontario, Mario Tomasello, Maurizio Uva, Luigi Maiolino, Edward J Calabrese, Salvatore Cuzzocrea, Vittorio Calabrese
Human life develops and expands not only in time and space, but also in the retrograde permanent recollection and interweaving of memories. Therefore, individual human identity depends fully on a proper access to the autobiographical memory. Such access is hindered or lost under pathological conditions such as Alzheimer's disease, including recently associated oxidant pathologies, such as ocular neural degeneration occurring in glaucoma or neurosensorial degeneration occurring in Menière's disease. Oxidative stress and altered antioxidant systems have been suggested to play a role in the aetiology of major neurodegenerative disorders, and altered expression of genes sensing oxidative stress, as well as decreased cellular stress response mechanisms could synergistically contribute to the course of these oxidant disorders...
2018: Immunity & Ageing: I & A
Isaac G Onyango
Alzheimer's disease (AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons...
January 2018: Neural Regeneration Research
Jordi Olloquequi, Elizabeth Cornejo-Córdova, Ester Verdaguer, Francesc X Soriano, Octavio Binvignat, Carme Auladell, Antoni Camins
Neurological and psychiatric disorders are leading contributors to the global disease burden, having a serious impact on the quality of life of both patients and their relatives. Although the molecular events underlying these heterogeneous diseases remain poorly understood, some studies have raised the idea of common mechanisms involved. In excitotoxicity, there is an excessive activation of glutamate receptors by excitatory amino acids, leading to neuronal damage. Thus, the excessive release of glutamate can lead to a dysregulation of Ca 2+ homeostasis, triggering the production of free radicals and oxidative stress, mitochondrial dysfunction and eventually cell death...
February 1, 2018: Journal of Psychopharmacology
Scott D Adams, Abbas Z Kouzani, Susannah J Tye, Kevin E Bennet, Michael Berk
Dynamic feedback based closed-loop medical devices offer a number of advantages for treatment of heterogeneous neurological conditions. Closed-loop devices integrate a level of neurobiological feedback, which allows for real-time adjustments to be made with the overarching aim of improving treatment efficacy and minimizing risks for adverse events. One target which has not been extensively explored as a potential feedback component in closed-loop therapies is mitochondrial function. Several neurodegenerative and psychiatric disorders including Parkinson's disease, Major Depressive disorder and Bipolar disorder have been linked to perturbations in the mitochondrial respiratory chain...
February 13, 2018: Journal of Neuroengineering and Rehabilitation
Azadeh Aminzadeh, Saeed Mehrzadi
Homocysteine (Hcy) is a major risk factor for vascular disease and is closely associated with endothelial dysfunction. Melatonin is a neurohormone that is mostly produced by the pineal gland. Studies have reported that melatonin exhibits neuroprotective effects in several neurodegenerative disorders. The aim of the current study was to investigate the possible protective effect of melatonin against Hcy-induced endothelial cell apoptosis in human umbilical vein endothelial cells (HUVECs) and to explore the underlying mechanisms...
February 13, 2018: Fundamental & Clinical Pharmacology
Alessandro Tozzi, Michela Tantucci, Saverio Marchi, Petra Mazzocchetti, Michele Morari, Paolo Pinton, Andrea Mancini, Paolo Calabresi
Parkinson's disease (PD) is a neurodegenerative disorder in which genetic and environmental factors synergistically lead to loss of midbrain dopamine (DA) neurons. Mutation of leucine-rich repeated kinase2 (Lrrk2) genes is responsible for the majority of inherited familial cases of PD and can also be found in sporadic cases. The pathophysiological role of this kinase has to be fully understood yet. Hyperactivation of Lrrk2 kinase domain might represent a predisposing factor for both enhanced striatal glutamatergic release and mitochondrial vulnerability to environmental factors that are observed in PD...
February 12, 2018: Cell Death & Disease
Cai-Xia Zang, Xiu-Qi Bao, Lin Li, Han-Yu Yang, Lu Wang, Yang Yu, Xiao-Liang Wang, Xin-Sheng Yao, Dan Zhang
Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. Although the exact causes of AD have not yet been fully elucidated, cholinergic dysfunction, mitochondrial damage, oxidative stress and neuroinflammation have been recognized as influential factors. Current drugs that are designed to address only a single target are unable to mitigate or prevent the progression of this complicated disease, so new disease-modifying drugs are urgently needed. Chinese herbs with thousand years of effective usage might be a good source for potential drugs...
February 12, 2018: American Journal of Chinese Medicine
Hao Zhang, Ping Wang, Yixue Xue, Libo Liu, Zhen Li, Yunhui Liu
In middle and old age, Alzheimer's disease (AD) is a progressive neurodegenerative disorder of brain. As an increasingly aging population, AD represents a huge burden for the patients' family and the country. However, current therapeutical strategies have shown limited effectiveness. Allicin, which is the main composition of garlic, was reported to prevent the learning and memory impairment of AD mouse model. As the mechanism is not clear, in this study, we used the APP (amyloid precursor protein)/PS1 (presenilin 1) double transgenic mice, which express human mutant APP and PS1, to determine the protective effect of allicin on neurons...
February 2018: Tissue & Cell
Zhihui Zhu, Georg Reiser
Small heat shock proteins (sHsps) are a group of proteins with molecular mass between 12 and 43 kDa. Currently, 11 members of this family have been classified, namely HspB1 to HspB11. HspB1, HspB2, HspB5, HspB6, HspB7, and HspB8, which are expressed in brain have been observed to be related to the pathology of neurodegenerative diseases, including Parkinson's, Alzheimer's, Alexander's disease, multiple sclerosis, and human immunodeficiency virus-associated dementia. Specifically, sHsps interact with misfolding and damaging protein aggregates, like Glial fibrillary acidic protein in AxD, β-amyloid peptides aggregates in Alzheimer's disease, Superoxide dismutase 1 in Amyotrophic lateral sclerosis and cytosine-adenine-guanine/polyglutamine (CAG/PolyQ) in Huntington's disease, Spinocerebellar ataxia type 3, Spinal-bulbar muscular atrophy, to reduce the toxicity or increase the clearance of these protein aggregates...
February 6, 2018: Neurochemistry International
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