Amyloid fibril structures and ferroptosis activation induced by ALS-causing SOD1 mutations

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Over 200 mutations in copper-zinc superoxide dismutase (SOD1) are associated with amyotrophic lateral sclerosis (ALS).
• Specific SOD1 mutants, H46R and G85R, show reduced metal ion binding capacity, a factor in ALS pathogenesis.
• Understanding the structural basis of SOD1 mutant aggregation is crucial for ALS research.

Purpose of the Study:

• To determine the cryo-electron microscopy structures of amyloid fibrils formed by H46R and G85R SOD1 mutants.
• To compare the structural characteristics and cytotoxicity of mutant SOD1 fibrils with wild-type SOD1 fibrils.
• To elucidate the mechanisms by which SOD1 mutant aggregation contributes to ALS pathology.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to resolve fibril structures.
• Biochemical assays to assess metal ion binding.
• Cell culture experiments to evaluate fibril toxicity, mitochondrial impairment, and ferroptosis induction.

Main Results:

• Novel cryo-EM structures of H46R and G85R SOD1 amyloid fibrils were obtained, revealing unique serpentine arrangements distinct from wild-type fibrils.
• The G85R fibril structure shows a core with seven or eight β strands, stabilized by a hydrophobic cavity and an R85-D101 salt bridge.
• Mutant SOD1 fibrils exhibited significantly higher toxicity, enhanced wild-type SOD1 aggregation, induced mitochondrial dysfunction, and activated ferroptosis in cell cultures.

Conclusions:

• SOD1 mutations associated with ALS can lead to the formation of distinct amyloid fibril structures.
• These mutant SOD1 fibrils possess unique structural features that enhance their cytotoxicity and propagation.
• The findings provide structural insights into how SOD1 mutations drive ALS pathogenesis through mitochondrial impairment and ferroptosis.