Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative motor neuron disorder.
Mutations in Cu,Zn superoxide dismutase (SOD1) cause approximately 20% of familial ALS. One of the possible mechanisms whereby
they induce disease is mitochondrial dysfunction in motor neurons. Here we describe
a patient with ALS and muscle mitochondrial oxidative defect associated with a novel
SOD1 mutation. Direct sequencing of SOD1 gene revealed a heterozygous mutation in codon 22 substituting a highly conserved
amino acid, from glutamine to arginine (Q22R). Muscle biopsy showed a neurogenic pattern
associated with cytochrome c oxidase (COX) deficiency in several muscle fibers. Western blot analysis demonstrated
a reduction in SOD1 content in the cytoplasmic and mitochondrial fractions. These results suggest that
a minute quantity of mutant SOD1 protein contributes to a mitochondrial toxicity also in muscle tissue.
Keywords
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References
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature. 1993; 362: 59-62
- Molecular biology of amyotrophic lateral sclerosis: insights from genetics.Nat Rev Neurosci. 2006; 7: 710-723
- Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria.Neuron. 2004; 43: 5-17
- Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria.Neuron. 2004; 43: 19-30
- Mitochondria take center stage in aging and neurodegeneration.Ann Neurol. 2005; 58: 495-505
- Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis.J Neurol Sci. 1998; 156: 65-72
- Visualization of defective mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis.J Neurol Sci. 1999; 169: 133-139
- Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis.Brain. 2000; 123: 1339-1348
- Amyotrophic lateral sclerosis with ragged-red fibers.Arch Neurol. 2008; 65: 403-406
- Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease.Ann Neurol. 1998; 43: 110-116
- Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes.Amyotroph Lateral Scler Other Mot Neuron Disord. 2003; 4: 62-73
- Absence of angiogenic genes modification in Italian ALS patients.Neurobiol Aging. 2008; 29: 314-316
- A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.Am J Hum Genet. 2004; 75: 822-831
- The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function.Brain. 2006; 129: 1710-1719
- Muscle biopsy, a practical approach (second ed.).Bailliere Tindal, London1985
- Cytochemistry and immunocytochemistry of mitochondria in tissue sections. Methods in enzymology. Academic Press Inc., 1996: 509-521
- Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels.J Neurol. 2002; 249: 305-311
- Ultrastructural localization of calcium binding sites on human muscle cell surface.Muscle Nerve. 1989; 12: 910-914
- Developmental and tissue-specific regulation of a novel dysferlin isoform.Muscle Nerve. 2004; 30: 366-374
- Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria.J Biol Chem. 2001; 276: 38388-38393
- Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria.Proc Natl Acad Sci USA. 2008; 105: 4022-4027
- Different regulation of wild type and mutant Cu,Zn superoxide dismutase localization in mammalian mitochondria.Hum Mol Genet. 2008 Aug 13; ([Elecronic publication ahead of print)
- Clinicopathological phenotype of ALS with a novel G72C SOD1 gene mutation mimicking a myopathy.Muscle Nerve. 2006; 33: 701-706
- Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation.J Neurochem. 2007; 102: 170-178
- Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice.J Biol Chem. 2002; 277: 29626-29633
- Lessons from models of SOD1-linked familial ALS..Trends Mol Med. 2004; : 393-400.
- Mitochondrial degeneration in amyotrophic lateral sclerosis.J Bioenerg Biomembr. 2004; 36: 395-399
- Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models.J Neurosci. 2006; 26: 4147-4154
- Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.Nat Genet. 1996; 13: 43-47
- Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia.J Neurosci. 1997; 17: 4180-4189
- Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation.Neuropathol. 2001; 21: 82-92
- Superoxide dismutase concentration and activity in familial amyotrophic lateral sclerosis.J Neurochem. 1995; 64: 2366-2369
Article info
Publication history
Accepted:
September 19,
2008
Received in revised form:
August 23,
2008
Received:
June 6,
2008
Identification
Copyright
© 2008 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
