Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor...

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Misfolded superoxide dismutase 1 (SOD1) species are implicated in amyotrophic lateral sclerosis (ALS) pathogenesis.
• Structurally independent SOD1 trimers, distinct from insoluble aggregates, are linked to increased cellular toxicity in ALS models.

Purpose of the Study:

• To investigate the molecular mechanisms underlying SOD1 trimer-induced cellular toxicity.
• To identify tissue-selective protein interactors and pathways affected by SOD1 trimers in the central nervous system and skeletal muscle.

Main Methods:

• Proteomics to map the SOD1 trimer interactome in brain, spinal cord, and skeletal muscle.
• Computational and biochemical analyses to characterize SOD1 trimer-protein binding, including interactions with septin-7.
• Gene enrichment analysis to identify affected cellular pathways.

Main Results:

• Identified a map of potential tissue-selective protein-binding partners for SOD1 trimers.
• Found that SOD1 trimers may disrupt normal cellular functions, including dendritic spine morphogenesis and synaptic function in the CNS, and cellular metabolism in skeletal muscle.
• Discovered SOD1 trimer-selective gene enrichment and characterized specific protein interactions, such as with septin-7.

Conclusions:

• SOD1 trimers interact with distinct proteins and pathways in a tissue-selective manner, offering insights into ALS pathology.
• These interactions suggest a convergence of genetic and pathophysiological mechanisms in ALS involving SOD1 trimers.
• The findings highlight potential therapeutic targets by revealing key proteins and pathways affected by SOD1 trimers.