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.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
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

Lillo, Concepcián (author)
Jonsson, Andreas P.Umeå universitet,Institutionen för medicinsk biovetenskap(Swepub:umu)aasjon95 (author)
Vande Velde, Christine (author)
Ward, Christopher M (author)
Miller, Timothy M (author)
Subramaniam, Jamuna R (author)
Rothstein, Jeffery D (author)
Marklund, StefanUmeå universitet,Klinisk kemi(Swepub:umu)stma0003 (author)
Andersen, Peter MUmeå universitet,Neurologi (author)
Brännström, ThomasUmeå universitet,Patologi(Swepub:umu)thbr0001 (author)
Gredal, Ole (author)
Wong, Philip C (author)
Williams, David S (author)
Cleveland, Don W (author)
Umeå universitetInstitutionen för medicinsk biovetenskap (creator_code:org_t)

By the author/editor: Liu, Jian; Lillo, Concepciá ...; Jonsson, Andreas ...; Vande Velde, Chr ...; Ward, Christophe ...; Miller, Timothy ...; show more...; Subramaniam, Jam ...; Rothstein, Jeffe ...; Marklund, Stefan; Andersen, Peter ...; Brännström, Thom ...; Gredal, Ole; Wong, Philip C; Williams, David ...; Cleveland, Don W; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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