Mitochondrial damage revealed by immunoselection for ALS-linked misfolded SOD1

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Mutant superoxide dismutase 1 (SOD1) is implicated in amyotrophic lateral sclerosis (ALS).
• A misfolded conformation of SOD1 is associated with disease toxicity.
• Misfolded SOD1 is found in affected tissues in SOD1-linked ALS models.

Purpose of the Study:

• To investigate the presence and role of misfolded SOD1 in spinal cord mitochondria in ALS.
• To correlate misfolded SOD1 with mitochondrial dysfunction.
• To examine misfolded SOD1 in patient-derived cells.

Main Methods:

• Utilized conformational antibodies (B8H10, C4F6) to detect misfolded SOD1.
• Employed flow cytometry to quantify SOD1 deposition on mitochondria.
• Analyzed mitochondrial morphology, superoxide production, and Bcl-2 exposure.
• Examined lymphoblast lysates and mitochondrial fractions from ALS patients and controls.

Main Results:

• Misfolded SOD1 (B8H10-reactive) was more abundant in mitochondria than oxidized SOD1 (C4F6-reactive).
• Age-dependent deposition of misfolded SOD1 on spinal cord mitochondria was observed in SOD1(G93A) rats and SOD1(G37R) mice.
• Mitochondrial damage parameters increased with the presence of misfolded SOD1.
• Misfolded SOD1 was detected in lymphoblasts from familial ALS patients with SOD1 mutations but not in controls.

Conclusions:

• Misfolded SOD1 is a common pathological feature in SOD1-mediated ALS rodent models and familial ALS patient lymphoblasts.
• Misfolded SOD1 is selectively associated with spinal cord mitochondria.
• Findings suggest a role for misfolded SOD1 in mitochondrial dysfunction during ALS pathogenesis.