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

Jagaraj, Cyril J.; Parakh, Sonam; Atkin, Julie D.

doi:10.3389/fncel.2020.581950

Cited by 21 publications

(14 citation statements)

References 393 publications

(291 reference statements)

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“…Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease categorized by progressive loss of upper and lower motor neurons [ 1 ]. It affects the motor neurons of the cerebral cortex, brainstem, and spinal cord in adults [ 2 – 4 ]. Individuals with ALS live with continuous and multiple functional losses, presenting upper, lower, and trunk muscle atrophy, muscle weakness, fasciculation, and subsequently progressive loss of all movements [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Cardiac Autonomic Modulation in Subjects with Amyotrophic Lateral Sclerosis (ALS) during an Upper Limb Virtual Reality Task: A Prospective Control Trial

Silveira

Moraes

Vidigal

et al. 2022

BioMed Research International

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. As a result of the rapid progression and severity of the disease, people with ALS experience loss of functionality and independence. Furthermore, it has already been described presence of autonomic dysfunction. Despite the increasing use of virtual reality (VR) in the treatment of different diseases, the use of virtual reality environment as an intervention program for ALS patients is innovative. The benefits and limitations have not yet been proven. Our objective was to evaluate the autonomic function of individuals with amyotrophic lateral sclerosis throughout the virtual reality task. The analysis of autonomic function was completed before, during, and after the virtual reality task using the upper limbs; also, all steps lasted ten minutes in a sitting position. Heart rate variability (HRV) was taken via the Polar® RS800CX cardiofrequencymeter. The following questionnaire was enforced: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS) and Fatigue Severity Scale (FSS). Different types of HRV were revealed for the groups, indicating that the ALS group has reduced HRV, with most of the representative indices of the sympathetic nervous system. Besides, the physiological process of reducing parasympathetic activity from rest to VR activity (vagal withdrawal), with reduction in HF (ms2) and an increase in HR from rest to activity, and a further increase throughout recovery, with withdrawal of sympathetic nervous system, occurs just for the control group (CG), with no alterations between rest, activity, and recovery in individuals with ALS. We could conclude that patients with ALS have the reduction of HRV with the sympathetic predominance when equated to the healthy CG. Besides that, the ALS individuals have no capability to adapt the autonomic nervous system when likened to the CG during therapy based on VR and their recovery.

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Section: Introductionmentioning

confidence: 99%

Cardiac Autonomic Modulation in Subjects with Amyotrophic Lateral Sclerosis (ALS) during an Upper Limb Virtual Reality Task: A Prospective Control Trial

Silveira

Moraes

Vidigal

et al. 2022

BioMed Research International

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“…ROS can damage neurons [ 58 ], and the ability of neuronal cells to maintain their normal redox state diminishes during aging [ 59 ]. Substantial evidence supports the critical importance of redox homeostasis in normal functioning of the nervous system [ 60 ], and redox dysregulation contributes to numerous neurodegenerative diseases [ 61 ]. Moreover, declining neuronal mitochondrial respiratory capacity may also contribute to NMJ degeneration, as Hayes et al have reported an age-dependent loss of mitochondria from motor neurons in Sod1 -/- mice [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Deletion of Neuronal CuZnSOD Accelerates Age-Associated Muscle Mitochondria and Calcium Handling Dysfunction That Is Independent of Denervation and Precedes Sarcopenia

Claflin

Huang

et al. 2021

IJMS

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Skeletal muscle suffers atrophy and weakness with aging. Denervation, oxidative stress, and mitochondrial dysfunction are all proposed as contributors to age-associated muscle loss, but connections between these factors have not been established. We examined contractility, mitochondrial function, and intracellular calcium transients (ICTs) in muscles of mice throughout the life span to define their sequential relationships. We performed these same measures and analyzed neuromuscular junction (NMJ) morphology in mice with postnatal deletion of neuronal Sod1 (i-mn-Sod1-/- mice), previously shown to display accelerated age-associated muscle loss and exacerbation of denervation in old age, to test relationships between neuronal redox homeostasis, NMJ degeneration and mitochondrial function. In control mice, the amount and rate of the decrease in mitochondrial NADH during contraction was greater in middle than young age although force was not reduced, suggesting decreased efficiency of NADH utilization prior to the onset of weakness. Declines in both the peak of the ICT and force were observed in old age. Muscles of i-mn-Sod1-/- mice showed degeneration of mitochondrial and calcium handling functions in middle-age and a decline in force generation to a level not different from the old control mice, with maintenance of NMJ morphology. Together, the findings support the conclusion that muscle mitochondrial function decreases during aging and in response to altered neuronal redox status prior to NMJ deterioration or loss of mass and force suggesting mitochondrial defects contribute to sarcopenia independent of denervation.

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“…Mitochondrial bioenergetics can also be affected in ALS [ 186 ]. According to this, examination of the ventral horn and the spinal motor neurons of ALS patients showed a significant decrease in MT-ND2 (Complex I) and MT-CO3 (Complex IV) genes, which could lead to the inhibition of ATP synthesis and motor neuronal degeneration [ 186 – 188 ]. Importantly, impairment of mitochondrial dynamics has been found in ALS, generating motor neuron toxicity and degeneration [ 19 , 185 , 189 , 190 ].…”

Section: Mitochondrial Dysfunction In Ad Pd Hd and Alsmentioning

confidence: 99%

The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders

Olesen

Villavicencio-Tejo

Quintanilla

2022

Transl Neurodegener

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Neurological disorders (NDs) are characterized by progressive neuronal dysfunction leading to synaptic failure, cognitive impairment, and motor injury. Among these diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) have raised a significant research interest. These disorders present common neuropathological signs, including neuronal dysfunction, protein accumulation, oxidative damage, and mitochondrial abnormalities. In this context, mitochondrial impairment is characterized by a deficiency in ATP production, excessive production of reactive oxygen species, calcium dysregulation, mitochondrial transport failure, and mitochondrial dynamics deficiencies. These defects in mitochondrial health could compromise the synaptic process, leading to early cognitive dysfunction observed in these NDs. Interestingly, skin fibroblasts from AD, PD, HD, and ALS patients have been suggested as a useful strategy to investigate and detect early mitochondrial abnormalities in these NDs. In this context, fibroblasts are considered a viable model for studying neurodegenerative changes due to their metabolic and biochemical relationships with neurons. Also, studies of our group and others have shown impairment of mitochondrial bioenergetics in fibroblasts from patients diagnosed with sporadic and genetic forms of AD, PD, HD, and ALS. Interestingly, these mitochondrial abnormalities have been observed in the brain tissues of patients suffering from the same pathologies. Therefore, fibroblasts represent a novel strategy to study the genesis and progression of mitochondrial dysfunction in AD, PD, HD, and ALS. This review discusses recent evidence that proposes fibroblasts as a potential target to study mitochondrial bioenergetics impairment in neurological disorders and consequently to search for new biomarkers of neurodegeneration.

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

Cited by 21 publications

References 393 publications

Cardiac Autonomic Modulation in Subjects with Amyotrophic Lateral Sclerosis (ALS) during an Upper Limb Virtual Reality Task: A Prospective Control Trial

Cardiac Autonomic Modulation in Subjects with Amyotrophic Lateral Sclerosis (ALS) during an Upper Limb Virtual Reality Task: A Prospective Control Trial

Deletion of Neuronal CuZnSOD Accelerates Age-Associated Muscle Mitochondria and Calcium Handling Dysfunction That Is Independent of Denervation and Precedes Sarcopenia

The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders

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