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The Role of Mitochondria, Oxidative Stress and Altered Calcium Homeostasis in Amyotrophic Lateral Sclerosis: From Current Developments in the Laboratory to Clinical Treatments

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889451463 Year: Pages: 336 DOI: 10.3389/978-2-88945-146-3 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2017-07-06 13:27:36
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Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, devastating and fatal disease characterized by selective loss of upper and lower motor neurons of the cerebral cortex, brainstem, spinal cord and muscle atrophy. In spite of many years of research, the pathogenesis of ALS is still not well understood. ALS is a multifaceted genetic disease, in which genetic susceptibility to motor neuron death interacts with environmental factors and there is still no cure for this deleterious disease. At present, there is only one FDA approved drug, Riluzole which according to past studies only modestly slows the progression of the disease, and improves survival by up to three months. The suffering of the ALS patients, and their families is enormous and the economic burden is colossal. There is therefore a pressing need for new therapies. Different molecular pathways and pathological mechanisms have been implicated in ALS. According to past studies, altered calcium homeostasis, abnormal mitochondrial function, protein misfolding, axonal transport defects, excessive production of extracellular superoxide radicals, glutamate-mediated excitotoxicity, inflammatory events, and activation of oxidative stress pathways within the mitochondria and endoplasmic reticulum can act as major contributor that eventually leads to loss of connection between muscle and nerve ultimately resulting to ALS. However, the detailed molecular and cellular pathophysiological mechanisms and origin and temporal progression of the disease still remained elusive. Ongoing research and future advances will likely advance our improve understanding about various involved pathological mechanism ultimately leading to discoveries of new therapeutic cures. Importantly, clinical biomarkers of disease onset and progression are thus also urgently needed to support the development of the new therapeutic agents and novel preventive and curative strategies. Effective translation from pre-clinical to clinical studies will further require extensive knowledge regarding drug activity, bioavailability and efficacy in both the pre-clinical and clinical setting, and proof of biological activity in the target tissue. During the last decades, the development of new therapeutic molecules, advance neuroimaging tools, patient derived induced stem cells and new precision medicine approaches to study ALS has significantly improved our understanding of disease. In particular, new genetic tools, neuroimaging methods, cellular probes, biomarker study and molecular techniques that achieve high spatiotemporal resolution have revealed new details about the disease onset and its progression. In our effort to provide the interested reader, clinician and researchers a comprehensive summaries and new findings in this field of ALS research, hereby we have created this electronic book which comprises of twenty seven chapters having various reviews, perspective and original research articles. All these chapters and articles in this book not only summarize the cutting-edge techniques, approaches, cell and animal models to study ALS but also provide unprecedented coverage of the current developments and new hypothesis emerging in ALS research. Some examples are novel genetic and cell culture based models, mitochondria-mediated therapy, oxidative stress and ROS mechanism, development of stem cells and mechanism-based therapies as well as novel biomarkers for designing and testing effective therapeutic strategies that can benefit ALS patients who are at the earlier stages in the disease. I am extremely grateful to all the contributors to this book and want to thank them for their phenomenal efforts. Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, devastating and fatal disease characterized by selective loss of upper and lower motor neurons of the cerebral cortex, brainstem, spinal cord and muscle atrophy. In spite of many years of research, the pathogenesis of ALS is still not well understood. ALS is a multifaceted genetic disease, in which genetic susceptibility to motor neuron death interacts with environmental factors and there is still no cure for this deleterious disease. At present, there is only one FDA approved drug, Riluzole which according to past studies only modestly slows the progression of the disease, and improves survival by up to three months. The suffering of the ALS patients, and their families is enormous and the economic burden is colossal. There is therefore a pressing need for new therapies. Different molecular pathways and pathological mechanisms have been implicated in ALS. According to past studies, altered calcium homeostasis, abnormal mitochondrial function, protein misfolding, axonal transport defects, excessive production of extracellular superoxide radicals, glutamate-mediated excitotoxicity, inflammatory events, and activation of oxidative stress pathways within the mitochondria and endoplasmic reticulum can act as major contributor that eventually leads to loss of connection between muscle and nerve ultimately resulting to ALS. However, the detailed molecular and cellular pathophysiological mechanisms and origin and temporal progression of the disease still remained elusive. Ongoing research and future advances will likely advance our improve understanding about various involved pathological mechanism ultimately leading to discoveries of new therapeutic cures. Importantly, clinical biomarkers of disease onset and progression are thus also urgently needed to support the development of the new therapeutic agents and novel preventive and curative strategies. Effective translation from pre-clinical to clinical studies will further require extensive knowledge regarding drug activity, bioavailability and efficacy in both the pre-clinical and clinical setting, and proof of biological activity in the target tissue. During the last decades, the development of new therapeutic molecules, advance neuroimaging tools, patient derived induced stem cells and new precision medicine approaches to study ALS has significantly improved our understanding of disease. In particular, new genetic tools, neuroimaging methods, cellular probes, biomarker study and molecular techniques that achieve high spatiotemporal resolution have revealed new details about the disease onset and its progression. In our effort to provide the interested reader, clinician and researchers a comprehensive summaries and new findings in this field of ALS research, hereby we have created this electronic book which comprises of twenty seven chapters having various reviews, perspective and original research articles. All these chapters and articles in this book not only summarize the cutting-edge techniques, approaches, cell and animal models to study ALS but also provide unprecedented coverage of the current developments and new hypothesis emerging in ALS research. Some examples are novel genetic and cell culture based models, mitochondria-mediated therapy, oxidative stress and ROS mechanism, development of stem cells and mechanism-based therapies as well as novel biomarkers for designing and testing effective therapeutic strategies that can benefit ALS patients who are at the earlier stages in the disease. I am extremely grateful to all the contributors to this book and want to thank them for their phenomenal efforts.

DNA Replication Stress

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ISBN: 9783039213894 9783039213900 Year: Pages: 368 DOI: 10.3390/books978-3-03921-390-0 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Science (General) --- Biology
Added to DOAB on : 2019-12-09 16:10:12
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Abstract

This Special Issue of International Journal of Molecular Sciences (IJMS) is dedicated to the mechanisms mediated at the molecular and cellular levels in response to adverse genomic perturbations and DNA replication stress. The relevant proteins and processes play paramount roles in nucleic acid transactions to maintain genomic stability and cellular homeostasis. A total of 18 articles are presented which encompass a broad range of highly relevant topics in genome biology. These include replication fork dynamics, DNA repair processes, DNA damage signaling and cell cycle control, cancer biology, epigenetics, cellular senescence, neurodegeneration, and aging. As Guest Editor for this IJMS Special Issue, I am very pleased to offer this collection of riveting articles centered on the theme of DNA replication stress. The blend of articles builds upon a theme that DNA damage has profound consequences for genomic stability and cellular homeostasis that affect tissue function, disease, cancer, and aging at multiple levels and through unique mechanisms. I thank the authors for their excellent contributions, which provide new insight into this fascinating and highly relevant area of genome biology.

Keywords

barley --- chromosome --- DNA replication pattern --- EdU --- mutagens --- DNA replication --- DNA damage --- DNA repair --- genome integrity --- A549 cells --- H1299 cells --- heterogeneity --- DNA damage response --- 8-chloro-adenosine --- DNA replication --- S phase --- origin firing --- TopBP1 --- ATR --- DNA fiber assay --- APE2 --- ATR-Chk1 DDR pathway --- Genome integrity --- SSB end resection --- SSB repair --- SSB signaling --- DNA replication stress --- genome stability --- ubiquitin --- replication fork restart --- translesion synthesis --- template-switching --- homologous recombination --- Fanconi Anemia --- G protein-coupled receptor (GPCR) --- aging --- DNA damage --- ?-arrestin --- G protein-coupled receptor kinase (GRK) --- interactome --- G protein-coupled receptor kinase interacting protein 2 (GIT2) --- ataxia telangiectasia mutated (ATM) --- clock proteins --- energy metabolism --- neurodegeneration --- cellular senescence --- ageing --- Alzheimer’s disease --- multiple sclerosis --- Parkinson’s disease --- lipofuscin --- SenTraGorTM (GL13) --- senolytics --- DNA replication --- DNA repair --- DNA damage response --- DNA translocation --- DNA helicase --- superfamily 2 ATPase --- replication restart --- fork reversal --- fork regression --- chromatin remodeler --- C9orf72 --- ALS --- motor neuron disease --- R loops, nucleolar stress --- neurodegeneration --- Difficult-to-Replicate Sequences --- replication stress --- non-B DNA --- Polymerase eta --- Polymerase kappa --- genome instability --- common fragile sites --- Microsatellites --- cancer --- DNA double-strand repair --- premature aging --- post-translational modification --- protein stability --- replication stress --- Werner Syndrome --- Werner Syndrome Protein --- dormant origins --- replicative stress --- replication timing --- DNA damage --- genome instability --- cancer --- Thermococcus eurythermalis --- endonuclease IV --- AP site analogue --- spacer --- DNA repair --- DNA repair --- double strand break repair --- exonuclease 1 --- EXO1 --- mismatch repair --- MMR --- NER --- nucleotide excision repair --- strand displacements --- TLS --- translesion DNA synthesis --- POL? --- mutation frequency --- mutations spectra --- SupF --- mutagenicity --- oxidative stress --- DNA damage --- DNA repair --- replication --- 8-oxoG --- epigenetic --- gene expression --- helicase --- cell cycle checkpoints --- genomic instability --- G2-arrest --- cell death --- repair of DNA damage --- adaptation --- n/a

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