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Oxidative stress and mitochondrial damage: importance in non-SOD1 ALS.

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TLDR
New evidence indicates that MD and OS play a role also in non-SOD1 ALS and thus they may represent a target for therapy despite previous failures in clinical trials.
Abstract
It is well known that mitochondrial damage (MD) is both the major contributor to oxidative stress (OS) (the condition arising from unbalance between production and removal of reactive oxygen species) and one of the major consequences of OS, because of the high dependance of mitochondrial function on redox-sensitive targets such as intact membranes. Conditions in which neuronal cells are not able to cope with MD and OS seem to lead or contribute to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), at least in the most studied superoxide dismutase 1 (SOD1)-linked genetic variant. As summarized in this review, new evidence indicates that MD and OS play a role also in non-SOD1 ALS and thus they may represent a target for therapy despite previous failures in clinical trials.

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A comprehensive review of amyotrophic lateral sclerosis.

TL;DR: This study provides a comprehensive review of ALS covering all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management.
Journal ArticleDOI

Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.

TL;DR: The roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS, its amyloid-like in vitro aggregation, its physiological vs. pathological oligomerization in vivo, liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP -43 inclusions are discussed.
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Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade

TL;DR: Possible therapeutic targets in Alzheimer's disease, Parkinson's Disease, and amyotrophic lateral sclerosis are outlined and molecules, previously designed or discovered as potential drug candidates for these disorders with emphasis on multifunctionality are discussed.
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Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease.

TL;DR: Current knowledge of the roles of lipid metabolism and function in the CNS are reviewed and how modulating these pathways may offer novel therapeutic options for treating ALS is discussed.
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Nrf2 in health and disease: current and future clinical implications

TL;DR: The present review summarizes promising findings from basic research and shows which Nrf2-targeting therapies are currently being investigated in clinical trials and which agents have already entered clinical practice.
References
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Journal ArticleDOI

Sirtuin 3, a New Target of PGC-1α, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis

TL;DR: It is shown that Sirt3 functions as a downstream target gene of PGC-1α and mediates the P GC-1 α effects on cellular ROS production and mitochondrial biogenesis, and integrates cellular energy metabolism and ROS generation.
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Wild-Type Human TDP-43 Expression Causes TDP-43 Phosphorylation, Mitochondrial Aggregation, Motor Deficits, and Early Mortality in Transgenic Mice

TL;DR: Transgenic mice expressing full-length human TDP-43 (hTDP- 43) driven by the mouse prion promoter are generated to provide a tool to analyze the role of wild-type hT DP-43 in the brain and spinal cord and for studying TDP -43-associated neurotoxicity.
Journal ArticleDOI

Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules.

TL;DR: A novel ALS truncation mutant (R495X) is reported that leads to a relatively severe ALS clinical phenotype compared with FUS missense mutations, and a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS is demonstrated.
Journal ArticleDOI

TDP-43 is recruited to stress granules in conditions of oxidative insult.

TL;DR: It is proved that TDP‐43 is not necessary for SG formation, and its gene silencing does not impair cell survival during stress, and an altered control of mRNA translation in stressful conditions may trigger motor neuron degeneration at early stages of the disease.
Journal ArticleDOI

ER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43

TL;DR: It is demonstrated that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER–mitochondria associations and that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER–Mitochondria interactions.
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