Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria

• One cause of amyotrophic lateral sclerosis (ALS) is mutation in ubiquitously expressed copper/zinc superoxide dismutase (SOD1), but the mechanism of toxicity to motor neurons is unknown. Multiple disease-causing mutants, but not wild-type SOD1, are now demonstrated to be recruited to mitochondria, but only in affected tissues. This is independent of the copper chaperone for SOD1 and dismutase activity. Highly preferential association with spinal cord mitochondria is seen in human ALS for a mutant SOD1 that accumulates only to trace cytoplasmic levels. Despite variable proportions that are successfully imported, nearly constant amounts of SOD1 mutants and covalently damaged adducts of them accumulate as apparent import intermediates and/or are tightly aggregated or crosslinked onto integral membrane components on the cytoplasmic face of those mitochondria. These findings implicate damage from action of spinal cord-specific factors that recruit mutant SOD1 to spinal mitochondria as the basis for their selective toxicity in ALS.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Aging/metabolism

Animals

Cytoplasm/metabolism

Disease Models

Animal

Humans

Intracellular Membranes/enzymology/pathology/ultrastructure

Macromolecular Substances

Mice

Mice

Transgenic

Microscopy

Electron

Mitochondria/*enzymology/genetics/pathology

Mitochondrial Proteins/metabolism

Molecular Chaperones/metabolism

Motor Neuron Disease/*enzymology/genetics/pathology

Mutation/genetics

Nerve Degeneration/*enzymology/genetics/physiopathology

Protein Binding/genetics

Protein Folding

Protein Isoforms/genetics/metabolism

Protein Transport/genetics

Spinal Cord/chemistry/*enzymology/pathology

Superoxide Dismutase/genetics/*metabolism/*toxicity

Publikations- och innehållstyp

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