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Updated: Jun 19, 2025
Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells
Published on: October 4, 2017
Trehalose Protects against Superoxide Dismutase 1 Proteinopathy in an Amyotrophic Lateral Sclerosis Model
Rayne S S Magalhães1, José R Monteiro Neto1, Gabriela D Ribeiro1
1Institute of Chemistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-901, Brazil.
Abstract:
This work aimed to study the effect of trehalose in protecting cells against Sod1 proteinopathy associated with amyotrophic lateral sclerosis (ALS). Humanized yeast cells in which native Sod1 was replaced by wild-type human Sod1 or an ALS mutant (WT-A4V Sod1 heterodimer) were used as the experimental model. Cells were treated with 10% trehalose (p/v) before or after the appearance of hSod1 proteinopathy induced by oxidative stress. In both conditions, trehalose reduced the number of cells with Sod1 inclusions, increased Sod1 activity, and decreased the levels of intracellular oxidation, demonstrating that trehalose avoids Sod1 misfolding and loss of function in response to oxidative stress. The survival rates of ALS Sod1 cells stressed in the presence of trehalose were 60% higher than in their absence. Treatment with trehalose after the appearance of Sod1 inclusions in cells expressing WT Sod1 doubled longevity; after 5 days, non-treated cells did not survive, but 15% of cells treated with sugar were still alive. Altogether, our results emphasize the potential of trehalose as a novel therapy, which might be applied preventively in ALS patients with a family history of the disease or after diagnosis in ALS patients who discover the disease following the first symptoms.
Insights
Trehalose protects against amyotrophic lateral sclerosis (ALS) by preventing harmful Sod1 protein misfolding and aggregation. This sugar compound enhances cell survival and Sod1 activity, offering a potential therapeutic strategy for ALS.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease often linked to mutations in the superoxide dismutase 1 (Sod1) gene.
- Sod1 proteinopathy, including misfolding and aggregation, is a key pathological feature in some forms of ALS.
- Oxidative stress exacerbates Sod1 proteinopathy, contributing to neuronal dysfunction and cell death.
Purpose of the Study:
- To investigate the protective effects of trehalose against Sod1 proteinopathy in a cellular model of ALS.
- To determine if trehalose can prevent or mitigate Sod1 misfolding, aggregation, and loss of function induced by oxidative stress.
- To evaluate the impact of trehalose on cell survival and Sod1 activity in the context of ALS-associated proteinopathy.
Main Methods:
- Utilized humanized yeast cells engineered to express either wild-type human Sod1 or an ALS-linked mutant (WT-A4V Sod1 heterodimer).
- Induced Sod1 proteinopathy through oxidative stress and treated cells with 10% trehalose, both before and after the onset of pathology.
- Quantified Sod1 inclusions, Sod1 enzymatic activity, intracellular oxidation levels, and cell survival rates.
Main Results:
- Trehalose treatment significantly reduced the formation of Sod1 inclusions in yeast cells under oxidative stress.
- The presence of trehalose increased Sod1 enzymatic activity and decreased intracellular oxidation levels, indicating protection against oxidative damage.
- Cell survival rates were substantially higher in trehalose-treated ALS Sod1 cells compared to untreated controls, with a 60% increase observed.
- Post-symptom treatment with trehalose in Sod1 inclusion-bearing cells doubled longevity, with 15% survival after 5 days versus 0% for controls.
Conclusions:
- Trehalose demonstrates significant potential as a therapeutic agent for amyotrophic lateral sclerosis (ALS) by mitigating Sod1 proteinopathy.
- The compound effectively prevents Sod1 misfolding and loss of function, while also enhancing cell survival under oxidative stress conditions.
- Trehalose could be considered for both preventive therapy in individuals with a family history of ALS and as a treatment after symptom onset.
