A JOURNAL OF NEUROLOGY
SOD1 targeted to the mitochondrial
intermembrane space prevents motor
neuropathy in the Sod1 knockout mouse
Lindsey R. Fischer,1,* Anissa Igoudjil,2,* Jordi Magrane ´,2Yingjie Li,1Jason M. Hansen,3
Giovanni Manfredi2and Jonathan D. Glass1
1 Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
2 Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA
3 Department of Paediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
*These authors contributed equally to this work.
Correspondence to: Jonathan D. Glass,
Emory Centre for Neurodegenerative Disease,
101 Woodruff Circle,
Suite 6000, Atlanta,
GA 30322, USA
Motor axon degeneration is a critical but poorly understood event leading to weakness and muscle atrophy in motor neuron
diseases. Here, we investigated oxidative stress-mediated axonal degeneration in mice lacking the antioxidant enzyme, Cu,Zn
superoxide dismutase (SOD1). We demonstrate a progressive motor axonopathy in these mice and show that Sod1?/?primary
motor neurons extend short axons in vitro with reduced mitochondrial density. Sod1?/?neurons also show oxidation of mito-
chondrial—but not cytosolic—thioredoxin, suggesting that loss of SOD1 causes preferential oxidative stress in mitochondria, a
primary source of superoxide in cells. SOD1 is widely regarded as the cytosolic isoform of superoxide dismutase, but is also
found in the mitochondrial intermembrane space. The functional significance of SOD1 in the intermembrane space is unknown.
We used a transgenic approach to express SOD1 exclusively in the intermembrane space and found that mitochondrial SOD1 is
sufficient to prevent biochemical and morphological defects in the Sod1?/?model, and to rescue the motor phenotype of these
mice when followed to 12 months of age. These results suggest that SOD1 in the mitochondrial intermembrane space is
fundamental for motor axon maintenance, and implicate oxidative damage initiated at mitochondrial sites in the pathogenesis
of motor axon degeneration.
Keywords: SOD; axon; neuromuscular junction; motor neuron disease; mitochondria
Abbreviations: O2??= superoxide; SOD1 = Cu,Zn superoxide dismutase
Motor axons are the anatomical and functional link between spinal
motor neurons and skeletal muscles. Degeneration of motor axons
at the neuromuscular junction is an early feature of motor neuron
disease in animal models (reviewed in Fischer and Glass, 2007)
and in humans (Bjornskov et al., 1984; Maselli et al., 1993).
Moreover, axonal degeneration is sufficient to cause weakness
doi:10.1093/brain/awq314 Brain 2011: 134; 196–209 |
Received June 27, 2010. Revised August 18, 2010. Accepted September 11, 2010. Advance Access publication November 14, 2010
? The Author (2010). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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and muscle atrophy, even in the absence of motor neuron cell
death (Gould et al., 2006; Rouaux et al., 2007; Suzuki et al.,
2007). Axon degeneration is therefore a key pathologic event
and therapeutic target in motor neuron disease, although the
pathogenic mechanisms that initiate axon degeneration are
Evidence from Cu,Zn superoxide dismutase (SOD1) knockout
mice suggests that this antioxidant enzyme is essential for motor
axon maintenance. Sod1?/?mice develop normally and lack
behavioural deficits up to 6 months of age (Reaume et al.,
1996), but ageing Sod1?/?mice perform poorly on the Rotarod
and exhibit accelerated skeletal muscle atrophy (Muller et al.,
2006). Spinal motor neuron and ventral root axon numbers are
normal at 17 and 19 months, respectively (Flood et al., 1999;
Shefner et al., 1999), but muscle fibre atrophy and fibre-type
grouping, suggestive of chronic denervation and reinnervation,
are detectable by 6 months (Flood et al., 1999). EMG recordings
also show spontaneous activity and progressive loss of motor units
(Shefner et al., 1999). Thus, genetic deletion of SOD1 spares
motor neurons and proximal axons, but may be detrimental to
distal motor axons.
SOD1 is one of three superoxide dismutases in mammalian cells
that catalyse the conversion of superoxide (O2??) to H2O2
(McCord and Fridovich, 1969). SOD1 is traditionally considered
to be the cytoplasmic isoform, SOD2 the mitochondrial isoform
and SOD3 the secreted form (Zelko et al., 2002). However, SOD1
is also found in the mitochondrial intermembrane space (Weisiger
and Fridovich, 1973; Sturtz
Vijayvergiya et al., 2005). The functional significance of SOD1
in the intermembrane space remains to be defined, although a
protective role is likely. Mitochondria isolated from Sod1?/?
mouse muscle (Muller et al., 2007; Jang et al., 2010) and
Sod1?/?Caenorhabditis elegans (Yanase et al., 2009) exhibit
increased generation of reactive oxygen species including O2??
and H2O2. Similarly, antisense knockdown of SOD1 in vitro
causes preferential oxidation of mitochondrial—not cytosolic—
proteins, loss of mitochondrial membrane potential and decreased
ATP production (Aquilano et al., 2006). Thus, loss of SOD1 may
result in an accumulation of mitochondrial reactive oxygen species,
leading to oxidative damage and mitochondrial dysfunction.
Here, we demonstrate that targeted replacement of SOD1 only
in the mitochondrial intermembrane space rescues motor axon
outgrowth and normalizes the mitochondrial redox state in
Sod1?/?neurons in vitro, and prevents weakness and neuro-
muscular junction denervation in Sod1?/?mice followed up to
12 months of age. These data suggest that mitochondrial oxida-
tive stress is an underlying cause of distal motor axonopathy, and
demonstrate that localization of SOD1 in the intermembrane
space is sufficient for the survival of motor axons.
et al., 2001; In ˜arrea,2002;
Materials and methods
Sod1?/?mice, generated by Huang and colleagues (1997), were
obtained from Marie Csete (Emory University) (Muller et al., 2006).
Sod1?/?males were crossed with thy1-YFP16 females (Feng et al.,
2000) to obtain Sod1+/?, thy1-YFP16 breeders, expressing yellow
fluorescent protein (YFP) in all motor axons. Both transgenic lines
were in a C57BL/6 background. For ease of description, thy1-YFP16
is omitted from the genotype and expression should be assumed. Mice
were housed in microisolator cages on a 12h light–dark cycle and
given free access to food and water. Genotyping was by standard
polymerase chain reaction analysis on tail-snip DNA. YFP status was
determined by fluorescent examination of epidermal nerve fibres in ear
To generate mitoSOD1 transgenic mice, human SOD1 complemen-
tary DNA was inserted in a prion promoter vector (MoPrP.Xho)
(Borchelt et al., 1996) at the XhoI site, between PrP exons 2 and 3.
The start codon of human SOD1 was removed and substituted by an
in-frame DNA linker of 6 nt, containing a BamHI site and coding for
Gly–Ser. We then inserted a 561nt complementary DNA encoding the
first 187 amino acids of mouse mitofilin (GenBank accession code:
NM_029673) (John et al., 2005) in frame with the 50-end of the
human SOD1 plus linker. The mitofilin complementary DNA was ob-
tained by polymerase chain reaction amplification of a mouse comple-
mentary DNA library using primer sequences derived from the mouse
The plasmid was microinjected into fertilized eggs of B6CBF1 mice.
Offspring harbouring the transgene were identified by polymerase
chain reaction using the following primers: CCGCTCGAGATGCTGCG
GGCGTGTCAG (sense) and CCGCTCGAGTTATTGGGCGATCCCAAT
(antisense) to generate a 1027bp product. Five lines of mitoSOD1
transgenic mice were identified. Male founders were crossed with
B6SJLF1/J females (Jackson).
A two-step mating scheme was used to generate mice expressing
only mitoSOD1. Sod1?/?males were crossed with mitoSOD1 females
to generate F1 heterozygotes (mitoSOD1,Sod1+/?). Sod1+/?and
mitoSOD1,Sod1+/?mice were then crossed to generate the target
genotype (mitoSOD1,Sod1?/?) and littermate controls.
Neuromuscular junction morphology
Tibialis anterior muscle was dissected, pinned in mild stretch and
immersion fixed for 30min in 4% paraformaldehyde at room tempera-
ture. Fixed muscles were cryoprotected in 30% sucrose/phosphate-
buffered saline (48–72h at 4?C), flash frozen in supercooled isopentane
and 35mm frozen sections were cut longitudinally through the entire
muscle. Acetylcholine receptors at the motor endplate were labelled
with Alexa Fluor 555-conjugated a-bungarotoxin (Invitrogen), 1:5000
in phosphate-buffered saline (30min, room temperature). Motor axon
terminals were identified by YFP fluorescence. Innervated, intermediate
and denervated endplates were defined by complete, partial or absent
overlap between nerve terminal and endplate, respectively. All endplates
were evaluated in every fourth section. No difference was seen between
innervation in male and female mice, therefore the data were pooled.
Mitochondrial isolation from mouse
Tissues (brain and spinal cord) were homogenized in a Dounce hom-
ogenizer in MS-EGTA buffer (225mM mannitol, 75mM sucrose,
5mM HEPES, 1mM EGTA, pH 7.4), and centrifuged at 2000g for
5min (4?C). The supernatant was centrifuged at 15000g for 20min to
generate the cytosolic fraction (supernatant) and crude mitochondrial
fraction (pellet). Thecytosolic
(22000g for 20min) to eliminate membrane contamination. The crude
fraction wascentrifuged twice
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Mitochondrial SOD1 protects motor axons Brain 2011: 134; 196–209 |