S-nitrosothiol depletion in amyotrophic lateral sclerosis

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Protein S-nitrosylation (SNO) is crucial for cellular function; dysregulation is linked to disease.
• Denitrosylases remove S-nitrosyl groups, and their activity impacts SNO homeostasis.
• Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS).

Purpose of the Study:

• To investigate the impact of SOD1 mutations on SNO homeostasis in ALS.
• To determine if altered denitrosylase activity of SOD1 contributes to SNO depletion in ALS.
• To explore the therapeutic potential of SNO-repleting compounds in ALS models.

Main Methods:

• Utilized cell and animal models expressing mutant SOD1.
• Assessed intracellular protein and peptide S-nitrosylation levels.
• Examined mitochondrial SNO levels and the function of S-nitrosylation-regulated proteins.
• Tested the efficacy of SNO donor compounds in rescuing cells.

Main Results:

• Mutant SOD1 exhibits increased denitrosylase activity, leading to reduced SNO levels in cells and animals.
• Mitochondria are particularly affected by SNO depletion in SOD1 mutant models.
• Deficient S-nitrosylation impairs proteins like glyceraldehyde-3-phosphate dehydrogenase (GAPDH), contributing to ALS pathogenesis.
• SNO donor compounds effectively rescued cells from mutant SOD1-induced death.

Conclusions:

• Aberrant SNO depletion due to mutant SOD1 contributes to motor neuron death in ALS.
• Deficient S-nitrosylation may be a general pathogenic mechanism in various diseases.
• SNO donor compounds represent a promising therapeutic strategy for ALS and related disorders.