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      Oxidative stress, mitochondrial damage and neurodegenerative diseases

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          Abstract

          Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca 2+ homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative eases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.

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          Most cited references108

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          Ageing and neuronal vulnerability.

          Everyone ages, but only some will develop a neurodegenerative disorder in the process. Disease might occur when cells fail to respond adaptively to age-related increases in oxidative, metabolic and ionic stress, thereby resulting in the accumulation of damaged proteins, DNA and membranes. Determinants of neuronal vulnerability might include cell size and location, metabolism of disease-specific proteins and a repertoire of signal transduction pathways and stress resistance mechanisms. Emerging evidence on protein interaction networks that monitor and respond to the normal ageing process suggests that successful neural ageing is possible for most people, but also cautions that cures for neurodegenerative disorders are unlikely in the near future.
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            Missing pieces in the Parkinson's disease puzzle.

            Parkinson's disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology.
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              Calcium and neurodegeneration.

              When properly controlled, Ca2+ fluxes across the plasma membrane and between intracellular compartments play critical roles in fundamental functions of neurons, including the regulation of neurite outgrowth and synaptogenesis, synaptic transmission and plasticity, and cell survival. During aging, and particularly in neurodegenerative disorders, cellular Ca2+-regulating systems are compromised resulting in synaptic dysfunction, impaired plasticity and neuronal degeneration. Oxidative stress, perturbed energy metabolism and aggregation of disease-related proteins (amyloid beta-peptide, alpha-synuclein, huntingtin, etc.) adversely affect Ca2+ homeostasis by mechanisms that have been elucidated recently. Alterations of Ca2+-regulating proteins in the plasma membrane (ligand- and voltage-gated Ca2+ channels, ion-motive ATPases, and glucose and glutamate transporters), endoplasmic reticulum (presenilin-1, Herp, and ryanodine and inositol triphosphate receptors), and mitochondria (electron transport chain proteins, Bcl-2 family members, and uncoupling proteins) are implicated in age-related neuronal dysfunction and disease. The adverse effects of aging on neuronal Ca2+ regulation are subject to modification by genetic (mutations in presenilins, alpha-synuclein, huntingtin, or Cu/Zn-superoxide dismutase; apolipoprotein E isotype, etc.) and environmental (dietary energy intake, exercise, exposure to toxins, etc.) factors that may cause or affect the risk of neurodegenerative disease. A better understanding of the cellular and molecular mechanisms that promote or prevent disturbances in cellular Ca2+ homeostasis during aging may lead to novel approaches for therapeutic intervention in neurological disorders such as Alzheimer's and Parkinson's diseases and stroke.
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                Author and article information

                Journal
                Neural Regen Res
                Neural Regen Res
                NRR
                Neural Regeneration Research
                Medknow Publications & Media Pvt Ltd (India )
                1673-5374
                1876-7958
                25 July 2013
                : 8
                : 21
                : 2003-2014
                Affiliations
                [1 ] Department of Pharmacy, Hebei North University, Zhangjiakou 075000, Hebei Province, China
                [2 ] Life Science Research Center, Hebei North University, Zhangjiakou 075000, Hebei Province, China
                [3 ] Department of Human Anatomy and Cell Science, University of Manitoba, Manitoba R3E 0J9, Canada
                [4 ] Hebei University of Science and Technology, Shijiazhuang 050018, Hebei Province, China
                Author notes

                Chunyan Guo, Master, Professor.

                Chunyan Guo and Xueping Chen contributed equally to this work.

                Corresponding author: Danshen Zhang, Professor, Doctoral supervisor, Hebei University of Science and Technology, Shijiazhuang 050018, Hebei Province, China, zhangdan-shen2011@ 123456126.com . (N20120813001)

                Author contributions: Guo CY collected and analyzed the references, conceived and designed the study, and wrote the manuscript. Sun L retrieved the references. Chen XP retrieved the references and revised the manuscript. Zhang DS was responsible for conception and design. All authors approved the final version of the paper.

                Author statements: The manuscript is original, has not been submitted to or is not under consideration by another publication, has not been previously published in any language or any form, including electronic, and contains no disclosure of confidential information or authorship/patent application/funding source disputations.

                Article
                NRR-8-2003
                10.3969/j.issn.1673-5374.2013.21.009
                4145906
                25206509
                9e37cfb7-7946-4248-a89a-52f067e6e2c9
                Copyright: © Neural Regeneration Research

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 02 March 2013
                : 15 May 2013
                Categories
                Review Article

                neural regeneration,neurodegenerative diseases,alzheimer's disease,parkinson's disease,amyotrophic lateral sclerosis,oxidative stress,reactive oxygen species,mitochondrial damage,respiratory chain,grants-supported paper,neuroregeneration

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