scholarly journals Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis

2021 ◽  
Author(s):  
Tiziana Petrozziello ◽  
Evan A. Bordt ◽  
Alexandra N. Mills ◽  
Spencer E. Kim ◽  
Ellen Sapp ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Mitochondrial Fragmentation ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

scholarly journals Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Tiziana Petrozziello ◽  
Evan A. Bordt ◽  
Alexandra N. Mills ◽  
Spencer E. Kim ◽  
Ellen Sapp ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Hyperphosphorylated Tau ◽  
Post Mortem ◽  
Related Protein ◽  
Mitochondrial Fragmentation ◽  
Novel Strategy ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Recent evidence suggest that tau may be involved in ALS pathogenesis. Here, we demonstrated that hyperphosphorylated tau (pTau-S396) is mis-localized to synapses in human post-mortem motor cortex (mCTX) across ALS subtypes. Treatment with ALS synaptoneurosomes (SNs) derived from post-mortem mCTX, enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity in vitro. Furthermore, our findings revealed that pTau-S396 interacts with the pro-fission dynamin-related protein (DRP1), and similar to pTau-S396, DRP1 accumulated in ALS SNs across ALS subtypes. Lastly, reducing tau with a specific bifunctional degrader, QC-01-175, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS.

scholarly journals Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 901 ◽  
Author(s):  
Elena Obrador ◽  
Rosario Salvador ◽  
Rafael López-Blanch ◽  
Ali Jihad-Jebbar ◽  
Soraya L. Vallés ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Cell Types ◽  
T Cell Subsets ◽  
Cellular Interactions ◽  
Underlying Mechanisms ◽  
Different Cell Types ◽  
And Oxidative Stress ◽  
Different Levels ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.

Amyotrophic Lateral Sclerosis and Oxidative Stress: A Double-Blind Therapeutic Trial After Curcumin Supplementation

2018 ◽  
Vol 17 (10) ◽  
pp. 767-779 ◽  
Author(s):  
Lucia Chico ◽  
Elena Caldarazzo Ienco ◽  
Costanza Bisordi ◽  
Annalisa Lo Gerfo ◽  
Lucia Petrozzi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Control Group ◽  
Therapeutic Trial ◽  
Entire Study ◽  
Reducing Ability ◽  
Group A ◽  
Group B ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

Objective: To investigate the efficacy of curcumin oral supplementation (600 mg/day, Brainoil), a natural antioxidant compound, in Amyotrophic Lateral Sclerosis (ALS). Methods: Patients were randomized into two groups: Group A received placebo for 3 months, then Brainoil for the following 3 months, Group B took Brainoil for 6 months. The evaluations were conducted at basal (T0), after 3 months of double blinded Brainoil or placebo treatment (T1), and after the 3 month open-label phase (T2). Clinical evaluations and oxidative stress biomarkers, including oxidative protein products (AOPPs), ferric reducing ability (FRAP), total thiols (T-SH) and lactate, were evaluated, compared to a control group, during an incremental forearm exercise test. Results: Over the entire study Group B showed a stable score of the ALS-FRS-r which decreased in Group A (p<0.01), in parallel with a reduction of AOPPs (p<0.01) which was not detected into Group A. Also FRAP exercise values remained stable in Group B, while in Group A they were reduced without treatment at T1 (0.05<p<0.01), for then increase at T2 with introduction of therapy (p<0.05). In Group B T1>T0 exercise lactate was lower compared to Group A (p<0.01). Compared to controls, the whole ALS population showed a greater oxidative stress (p<0.001), those treated with curcumin (Group B) exhibiting decreased exercise AOPPs at T2 with values approaching those of controls. Conclusion: Although further studies are needed to confirm these data, treatment with curcumin shows encouraging results indicating a slight slowdown in disease progression, improving aerobic metabolism and oxidative damage, this also contributing to deepen knowledge into the pathogenic mechanisms of ALS.

Neuroprotective potential of adenyl cyclase/cAMP/CREB and mitochondrial CoQ10 activator in amyotrophic lateral sclerosis rats

2020 ◽  
Vol 16 ◽  
Author(s):  
Mohmmad Mamtaj Alam ◽  
Elijabeth Minj ◽  
Rajeshwar Kumar Yadav ◽  
Sidharth Mehan
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Drug Therapy ◽  
Therapeutic Approach ◽  
Methyl Mercury ◽  
Chronic Treatment ◽  
Adenyl Cyclase ◽  
Als Patients ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

Aim: To investigate neuroprotective potential of of forskolin (FSK) in combination with solanesol (SNL) along with clinically proven drugs (riluzole, baclofen, citalopram) on behavioral, molecular and neurochemical alterations in methyl mercury-induced amyotrophic lateral sclerosis (ALS) rats. Background: ALS is a motor neuron disease in which oxidative stress is the principle mechanism ofneuronal death which can be mimicked by the dominant mutations in an antioxidant enzyme SOD-1. Due to MeHg neurotoxicity, behavioral and neurochemical alterations occur in rats. During ALS mitochondrial CoQ10 dysfunctioning and downregulation of adenyl cyclase/CREB are major pathological hallmark for neurodegeneration in ALS. Clinically proven drug therapy comes with limited therapeutic involvement, and is used as approachable therapy in ALS patients. Objective: Therefore, current research explores the up-regulation of adenyl cyclase/cAMP/CREB by FSK 30, 60 mg/kg in combination with mitochondrial ETC-coenzyme-Q10 precursor SNL 15, 30 mg/kg can be a preventive therapeutic approach to overcome the ALS like symptoms. Method: MeHg (5 mg/kg) is a neurotoxic compound that leads to ALS like behavioral & neurochemical alterations. Results: Chronic treatment with the combination of FSK 30,60 mg/kg and SNL 15,30 mg/kg alone and along with standard drugs citalopram (5 mg/kg), riluzole (5 mg/kg) and baclofen (3 mg/kg) increased the adenyl cyclase and mitochondrial CoQ10 and ETC-complexes enzyme levels and shows the neuroprotective potential by significantly improving the cognitive deficitslocomotion, , grip strength, and restoration of neurochemicals alterations along with reducing the level of inflammatory mediators and oxidative stress in ALS rats. Conclusion: Thus, we concluded that FSK in combination with SNL along with standard drugs can be a possible therapeutic approach for the treatment of ALS.

scholarly journals Anti-inflammatory Effects of a Novel Herbal Extract in the Muscle and Spinal Cord of an Amyotrophic Lateral Sclerosis Animal Model

2021 ◽  
Vol 15 ◽  
Author(s):  
Sun Hwa Lee ◽  
Mudan Cai ◽  
Eun Jin Yang
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Herbal Extract ◽  
Motor Neuron Loss ◽  
Related Proteins ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a complex disease characterized by motor neuron loss and muscle atrophy. There is no prominent treatment for ALS as the pathogenic process in the skeletal muscle and spinal cord is complex and multifactorial. Therefore, we investigated the effects of a herbal formula on the multi-target effects in the skeletal muscle and spinal cord in hSOD1G93A transgenic mice. We prepared a herbal extract (HE) from Glycyrrhiza uralensis, Atractylodes macrocephala Koidzumi, Panax ginseng, and Astragalus membranaceus. Control and HE-treated mice underwent rotarod and footprint tests. We also performed immunohistochemical and Western blotting analyses to assess expression of inflammation-related and oxidative stress-related proteins in the muscle and spinal cord tissues. We found that the HE increased motor activity and reduced motor neuron loss in hSOD1G93A mice. In addition, the HE significantly reduced the levels of inflammatory proteins and oxidative stress-related proteins in the skeletal muscles and spinal cord of hSOD1G93A mice. Furthermore, we demonstrated that the HE regulated autophagy function and augmented neuromuscular junction in the muscle of hSOD1G93A mice. Based on these results, we propose that the HE formula may be a potential therapeutic strategy for multi-target treatment in complex and multifactorial pathological diseases.

Relationship between Liver Pathology and Disease Progression in a Murine Model of Amyotrophic Lateral Sclerosis

2018 ◽  
Vol 18 (4) ◽  
pp. 200-207 ◽  
Author(s):  
Sun Hwa  Lee ◽  
Eun Jin Yang
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Molecular Mechanisms ◽  
Lymphocytic Infiltration ◽  
Skeletal Muscle Atrophy ◽  
Muscle Pathology ◽  
Liver Pathology ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes selective motor neuron cell death and accompanying skeletal muscle atrophy and structural deformities. In both patients with ALS and animal models, there appears to be spinal cord and muscle pathology. This pathology can be modeled in hSOD1G93A mice, which have a point mutation in the gene for superoxide dismutase 1. Similar to patients with ALS, hSOD1G93A mice present hepatic abnormalities and lymphocytic infiltration in the liver. However, the relationship between liver function and disease progression is not well understood. Objective: The goal of this study was to investigate the molecular mechanisms relating liver pathology to disease progression in hSOD1G93A mice. Methods: Liver tissues were harvested from control (nontransgenic) mice, presymptomatic hSOD1G93A mice, and symptomatic hSOD1G93A mice. Results: In the liver, the expression of proteins related to inflammation and oxidative stress increased with disease progression in hSOD1G93A mice. Furthermore, histone deacetylase 4, DNA-damage-inducible 45α, and platelet-derived growth factor β, which are associated with liver fibrosis, were upregulated in the livers of presymptomatic hSOD1G93A mice. Conclusions: Taken together, these findings suggest that liver dysfunction in hSOD1G93A transgenic mice is mediated by increased inflammation and oxidative stress as well as the upregulation of fibrosis-related proteins.

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