Emerging Evidence Highlighting the Importance of Redox Dysregulation in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS)

The cellular redox state, or balance between cellular oxidation and reduction reactions, serves as a vital antioxidant defence system that is linked to all important cellular activities. Redox regulation is therefore a fundamental cellular process for aerobic organisms. Whilst oxidative stress is well described in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), other aspects of redox dysfunction and their contributions to pathophysiology are only just emerging. ALS is a fatal neurodegenerative disease affecting motor neurons, with few useful treatments. Hence there is an urgent need to develop more effective therapeutics in the future. Here, we discuss the increasing evidence for redox dysregulation as an important and primary contributor to ALS pathogenesis, which is associated with multiple disease mechanisms. Understanding the connection between redox homeostasis, proteins that mediate redox regulation, and disease pathophysiology in ALS, may facilitate a better understanding of disease mechanisms, and lead to the design of better therapeutic strategies.

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Redox Regulation in Amyotrophic Lateral Sclerosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/408681 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 46

Author(s):

Sonam Parakh ◽

Damian M. Spencer ◽

Mark A. Halloran ◽

Kai Y. Soo ◽

Julie D. Atkin

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Protein Misfolding ◽

Redox Regulation ◽

Stress Protein ◽

Glutamate Excitotoxicity ◽

Chaperone Protein ◽

Cellular Abnormalities ◽

Underlying Mechanisms ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER) stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI) could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS.

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Pathogenic Genome Signatures That Damage Motor Neurons in Amyotrophic Lateral Sclerosis

Cells ◽

10.3390/cells9122687 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2687

Author(s):

Ali Yousefian-Jazi ◽

YunHee Seol ◽

Jieun Kim ◽

Hannah L. Ryu ◽

Junghee Lee ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Genetic Variants ◽

Diagnostic Tests ◽

Neurodegenerative Disorder ◽

Therapeutic Approaches ◽

Causative Gene ◽

Disease Mechanisms ◽

Disease Modifying ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease and a neurodegenerative disorder, affecting the upper and/or lower motor neurons. Notably, it invariably leads to death within a few years of onset. Although most ALS cases are sporadic, familial amyotrophic lateral sclerosis (fALS) forms 10% of the cases. In 1993, the first causative gene (SOD1) of fALS was identified. With rapid advances in genetics, over fifty potentially causative or disease-modifying genes have been found in ALS so far. Accordingly, routine diagnostic tests should encompass the oldest and most frequently mutated ALS genes as well as several new important genetic variants in ALS. Herein, we discuss current literatures on the four newly identified ALS-associated genes (CYLD, S1R, GLT8D1, and KIF5A) and the previously well-known ALS genes including SOD1, TARDBP, FUS, and C9orf72. Moreover, we review the pathogenic implications and disease mechanisms of these genes. Elucidation of the cellular and molecular functions of the mutated genes will bring substantial insights for the development of therapeutic approaches to treat ALS.

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Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

Frontiers in Neuroscience ◽

10.3389/fnins.2021.783624 ◽

2021 ◽

Vol 15 ◽

Author(s):

Bridget C. Benson ◽

Pamela J. Shaw ◽

Mimoun Azzouz ◽

J. Robin Highley ◽

Guillaume M. Hautbergue

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Mitochondrial Function ◽

Research Effort ◽

Rna Metabolism ◽

Atp Production ◽

Neurodegenerative Process ◽

Progressive Degeneration ◽

Disease Mechanisms ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. As with the majority of neurodegenerative diseases, the pathological hallmarks of ALS involve proteinopathies which lead to the formation of various polyubiquitylated protein aggregates in neurons and glia. ALS is a highly heterogeneous disease, with both familial and sporadic forms arising from the convergence of multiple disease mechanisms, many of which remain elusive. There has been considerable research effort invested into exploring these disease mechanisms and in recent years dysregulation of RNA metabolism and mitochondrial function have emerged as of crucial importance to the onset and development of ALS proteinopathies. Widespread alterations of the RNA metabolism and post-translational processing of proteins lead to the disruption of multiple biological pathways. Abnormal mitochondrial structure, impaired ATP production, dysregulation of energy metabolism and calcium homeostasis as well as apoptosis have been implicated in the neurodegenerative process. Dysfunctional mitochondria further accumulate in ALS motor neurons and reflect a wider failure of cellular quality control systems, including mitophagy and other autophagic processes. Here, we review the evidence for RNA and mitochondrial dysfunction as some of the earliest critical pathophysiological events leading to the development of ALS proteinopathies, explore their relative pathological contributions and their points of convergence with other key disease mechanisms. This review will focus primarily on mutations in genes causing four major types of ALS (C9ORF72, SOD1, TARDBP/TDP-43, and FUS) and in protein homeostasis genes (SQSTM1, OPTN, VCP, and UBQLN2) as well as sporadic forms of the disease. Finally, we will look to the future of ALS research and how an improved understanding of central mechanisms underpinning proteinopathies might inform research directions and have implications for the development of novel therapeutic approaches.

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Exploring molecular approaches in Amyotrophic lateral sclerosis: Drug targets from clinical and pre-clinical findings

Current Molecular Pharmacology ◽

10.2174/1566524020666200427214356 ◽

2020 ◽

Vol 13 ◽

Author(s):

Mamtaj Alam ◽

Rajeshwar Kumar Yadav ◽

Elizabeth Minj ◽

Aarti Tiwari ◽

Sidharth Mehan

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Drug Targets ◽

Therapeutic Index ◽

Experimental Models ◽

Clinical Findings ◽

Adenyl Cyclase ◽

Molecular Approaches ◽

Pharmacologically Active ◽

Lateral Sclerosis

: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterised by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age included impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% beyond 10 years of age. The limited intervention of pharmacologically active compounds that are used clinically is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, current review specially targeted in the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with up-regulation of intracellular adenyl cyclase/cAMP/CREB and mitochondrial-ETC coenzyme-Q10 activation as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.

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Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

Current Neurovascular Research ◽

10.2174/1567202617666200409125227 ◽

2020 ◽

Vol 17 (3) ◽

pp. 275-285 ◽

Cited By ~ 5

Author(s):

Si Chen ◽

Qiao Liao ◽

Ke Lu ◽

Jinxia Zhou ◽

Cao Huang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Rat Model ◽

Microglial Activation ◽

Transgenic Rat ◽

Intragastric Administration ◽

Behavioral Deficits ◽

Als Patients ◽

Lateral Sclerosis ◽

Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

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Cortical and Striatal Electroencephalograms and Apomorphine Effects in the FUS Mouse Model of Amyotrophic Lateral Sclerosis

Journal of Alzheimer s Disease ◽

10.3233/jad-201472 ◽

2021 ◽

pp. 1-15

Author(s):

Vasily Vorobyov ◽

Alexander Deev ◽

Frank Sengpiel ◽

Vladimir Nebogatikov ◽

Aleksey A. Ustyugov

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Cortical Neurons ◽

Primary Motor Cortex ◽

Beta Activity ◽

Systemic Injection ◽

Eeg Spectra ◽

Electroencephalogram Eeg ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum. Objective: To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression. Methods: We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in ΔFUS(1–359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline. Results: In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice. Conclusion: We suggest that revealed EEG modifications in ΔFUS(1–359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations.

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Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case

BMC Neurology ◽

10.1186/s12883-021-02306-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Atsuhiko Sugiyama ◽

Takahiro Takeda ◽

Mizuho Koide ◽

Hajime Yokota ◽

Hiroki Mukai ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Repeat Expansion ◽

Cerebellar Hemisphere ◽

Intranuclear Inclusions ◽

Intranuclear Inclusion ◽

Neuronal Intranuclear Inclusion ◽

Lateral Sclerosis

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. Case presentation A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. Conclusions We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.

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The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

Cells ◽

10.3390/cells10081865 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1865

Author(s):

Nica Borgese ◽

Nicola Iacomino ◽

Sara Francesca Colombo ◽

Francesca Navone

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Adaptor Proteins ◽

Loss Of Function ◽

Membrane Contact Sites ◽

Physiological Processes ◽

Main Driver ◽

Single Allele ◽

Induced Pluripotent ◽

Lateral Sclerosis

The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca2+ signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease.

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The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

Journal of Personalized Medicine ◽

10.3390/jpm11070671 ◽

2021 ◽

Vol 11 (7) ◽

pp. 671

Author(s):

Oihane Pikatza-Menoio ◽

Amaia Elicegui ◽

Xabier Bengoetxea ◽

Neia Naldaiz-Gastesi ◽

Adolfo López de Munain ◽

...

Keyword(s):

Skeletal Muscle ◽

Amyotrophic Lateral Sclerosis ◽

Muscle Tissue ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Fine Tuning ◽

Current State ◽

The Central Nervous System ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

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Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis

Brain Sciences ◽

10.3390/brainsci11070906 ◽

2021 ◽

Vol 11 (7) ◽

pp. 906

Author(s):

Nimeshan Geevasinga ◽

Mehdi Van den Bos ◽

Parvathi Menon ◽

Steve Vucic

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Cortical Excitability ◽

Muscular Atrophy ◽

Close Relationship ◽

Bulbar Onset ◽

Als Patients ◽

Transcranial Magnetic Simulation ◽

Cortical Dysfunction ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.

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