scholarly journals Methylene blue inhibits nucleation and elongation of SOD1 amyloid fibrils

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9719
Author(s):  
Greta Musteikyte ◽  
Mantas Ziaunys ◽  
Vytautas Smirnovas
Keyword(s):  
Methylene Blue ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Late Onset ◽  
Amyloid Aggregation ◽  
Amyloidogenic Proteins ◽  
Lateral Sclerosis

Protein aggregation into highly-structured amyloid fibrils is linked to several neurodegenerative diseases. Such fibril formation by superoxide dismutase I (SOD1) is considered to be related to amyotrophic lateral sclerosis, a late-onset and fatal disorder. Despite much effort and the discovery of numerous anti-amyloid compounds, no effective cure or treatment is currently available. Methylene blue (MB), a phenothiazine dye, has been shown to modulate the aggregation of multiple amyloidogenic proteins. In this work we show its ability to inhibit both the spontaneous amyloid aggregation of SOD1 as well as elongation of preformed fibrils.

scholarly journals Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis

2020 ◽  
Author(s):  
Mengli Wang ◽  
Zhen Liu ◽  
Juan Du ◽  
Yanchun Yuan ◽  
Bin Jiao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Early Onset ◽  
Late Onset ◽  
Meta Analysis ◽  
Age At Onset ◽  
Serum Levels ◽  
Patient Groups ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Background: Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases.Methods: Serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson’s disease (PD), and 82 healthy controls (HCs). A meta-analysis including data from this study was performed to evaluate the differences in the levels of immunoglobulin and complement between ALS patients and HCs. The serum levels of immunoglobulin and complement were compared between patient groups and HCs or between ALS patient groups established by age at onset, site at onset, disease duration, or disease severity. The correlations between the levels of immunoglobulin and complement and the clinical characteristics of ALS were analysed using Spearman correlation analysis.Results: The pooled results showed that patients with ALS had higher C4 levels than did HCs, and no significant differences between these two groups in IgG, IgA, IgM, or C3 levels were found. Multiple comparisons revealed that there were no significant differences between patients with ALS and other neurodegenerative diseases in IgG, IgA, IgM, C3, or C4 levels. In addition, the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs. The correlations between age at onset of ALS and IgG and IgA levels were significantly positive. Moreover, spinal-onset ALS patients had lower serum IgG levels than did HCs, but no difference was found between bulbar-onset ALS patients and HCs.Conclusions: Peripheral immunity abnormalities existed in patients with ALS, and lower IgG levels were associated with early-onset ALS.

scholarly journals Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengli Wang ◽  
Zhen Liu ◽  
Juan Du ◽  
Yanchun Yuan ◽  
Bin Jiao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Late Onset ◽  
Meta Analysis ◽  
Age At Onset ◽  
Serum Levels ◽  
Als Patients ◽  
Immune Dysfunctions ◽  
Lateral Sclerosis

Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases. Therefore, we performed this study to address these gaps. In the present study, serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson's disease (PD), and 82 healthy controls (HCs). Multiple comparisons revealed that no significant differences existed between patients with ALS and other neurodegenerative diseases in immunoglobulin and complement levels. Meta-analysis based on data from our cohort and eight published articles was performed to evaluate the serum immunoglobulin and complement between patients with ALS and HCs. The pooled results showed that patients with ALS had higher C4 levels than HCs. In addition, we found that the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs, and the correlations between age at onset of ALS and IgG or IgA levels were significant positive. In conclusion, our data supplement existing literature on understanding the role of peripheral immunity in ALS.

scholarly journals The Antiaggregative and Antiamyloidogenic Properties of Nanoparticles: A Promising Tool for the Treatment and Diagnostics of Neurodegenerative Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Monika Pichla ◽  
Grzegorz Bartosz ◽  
Izabela Sadowska-Bartosz
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
High Throughput ◽  
Diagnostic Tool ◽  
Neurodegenerative Disorders ◽  
High Throughput Screening ◽  
Promising Tool ◽  
Socioeconomic Burden ◽  
Lateral Sclerosis

Due to the progressive aging of the society, the prevalence and socioeconomic burden of neurodegenerative diseases are predicted to rise. The most common neurodegenerative disorders nowadays, such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, can be classified as proteinopathies. They can be either synucleinopathies, amyloidopathies, tauopathies, or TDP-43-related proteinopathies; thus, nanoparticles with a potential ability to inhibit pathological protein aggregation and/or degrade already existing aggregates can be a promising approach in the treatment of neurodegenerative diseases. As it turns out, nanoparticles can be a double-edged sword; they can either promote or inhibit protein aggregation, depending on coating, shape, size, surface charge, and concentration. In this review, we aim to emphasize the need of a breakthrough in the treatment of neurodegenerative disorders and draw attention to nanomaterials, as they can also serve as a diagnostic tool for protein aggregates or can be used in a high-throughput screening for novel antiaggregative compounds.

scholarly journals Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43

2020 ◽  
Author(s):  
Qiuye Li ◽  
W. Michael Babinchak ◽  
Witold K Surewicz
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Amyloid Fibrils ◽  
Low Complexity ◽  
Structural Features ◽  
Protein Fragments ◽  
Structural Perturbations ◽  
Insight Into ◽  
Short Protein ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis and several other neurodegenerative diseases are associated with brain deposits of TDP-43 aggregates. Cryo-EM structure of amyloid formed from the entire TDP-43 low complexity domain reveals single protofilament fibrils containing a large (138-residue), tightly packed core with structural features that differ from those previously found for fibrils formed from short protein fragments. The atomic model provides insight into potential structural perturbations caused by phosphorylation and disease-related mutations.

scholarly journals Impaired Cu-Zn superoxide dismutase (SOD1) and calcineurin (Cn) interaction in ALS: A presumed consequence for TDP-43 and zinc aggregation in Tg SOD1G93A rodent spinal cord tissue

2017 ◽  
Author(s):  
Jolene M. Kim ◽  
Elizabeth Billington ◽  
Ada Reyes ◽  
Tara Notarianni ◽  
Jessica Sage ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Animal Models ◽  
Protein Aggregation ◽  
Phosphatase Activity ◽  
Spinal Cord Tissue ◽  
Protein Levels ◽  
Tissue Homogenates ◽  
Lateral Sclerosis

ABSTRACTImpaired interactions between Calcineurin (Cn) and (Cu/Zn) superoxide dismutase (SOD1) are suspected to be responsible for the formation of hyperphosphorylated protein aggregation in amyotrophic lateral sclerosis (ALS). Serine (Ser)-enriched TDP-43 protein aggregation appears in the spinal cord of ALS animal models, and may be linked to the reduced phosphatase activity of Cn. The mutant overexpressed SOD1G93A protein does not properly bind zinc (Zn) in animal models; hence, mutant SOD1G93A - Cn interaction weakens. Consequently, unstable Cn fails to dephosphorylate TDP-43 that yields hyperphosphorylated TDP-43 aggregates. Our previous studies had suggested that Cn and SOD1 interaction was necessary to keep Cn enzyme functional. We have observed low Cn level, increased Zn concentrations, and increased TDP-43 protein levels in cervical, thoracic, lumbar, and sacral regions of the spinal cord tissue homogenates. This study further supports our previous published work indicating that Cn stability depends on functional Cn-SOD1 interaction because Zn metal is crucial for maintaining the Cn stability. Less active Cn did not efficiently dephosphorylate TDP-43; hence TDP-43 aggregations appeared in the spinal cord tissue.

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