SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse

Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Brain (Impact Factor: 9.2). 11/2010; 134(Pt 1):196-209. DOI: 10.1093/brain/awq314
Source: PubMed


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 mitochondrial--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.

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    • "It has been suggested that both fast muscle and motor units are selectively vulnerable to the disease process in ALS patients [56] [57]. This increased sensitivity to muscle denervation in fast muscles has also been demonstrated in aged mice [27] [28] and SOD1-/- mice [35] [36]. A potential mechanism mediating muscle denervation in the G93A SOD1 mice may be increased oxidative stress resulting from transgenic expression of mutant SOD1 gene. "
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    ABSTRACT: Muscle denervation at the neuromuscular junction (NMJ) is thought to be a contrib-uting factor in age-related muscle weakness. Therefore, understanding the mechanisms that modulate NMJ innervation is a key to developing therapies to combat age-related muscle weakness affecting the elderly. Two mouse models, one lacking the Cu/Zn su-peroxide dismutase (SOD1) gene and another harboring the transgenic mutant human SOD1 gene, display progressive changes at the NMJ, including muscle endplate frag-mentation, nerve terminal sprouting, and denervation. These changes at the NMJ share many of the common features observed in the NMJs of aged mice. In this review, re-search findings demonstrating the effects of PGC-1α, IGF-1, GDNF, MyoD, myogenin, and miR-206 on NMJ innervation patterns in the G93A SOD1 mice will be highlighted in the context of age-related muscle denervation.
    Aging and Disease 05/2015; 6(6):xxxx. DOI:10.14336/AD.2015.0506 · 3.07 Impact Factor
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    • "o skeletal muscle using a conditional Sod1 knockout model caused no overt disruptions in synaptic transmission ( unpublished data ) or morphological denervation [ 42 ] . On the other hand , when CuZnSOD is ectopically expressed in neurons in the Sod1 2 / 2 mice , NMJ morphology and neurotransmission are fully rescued [ 29 ] . Moreover , a study by Fischer et al . ( 2011 ) showed that neuronal mitochondrial expression of CuZnSOD in Sod1 2 / 2 mice was sufficient to reverse the NMJ degeneration and loss of muscle mass [ 28 ] . Together these data strongly support an essential role for the control of superoxide levels in the presynaptic motor neurons by CuZnSOD in NMJ maintenance and function ."
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    ABSTRACT: Elevated reactive oxygen species (ROS) production and ROS-dependent protein damage is a common observation in the pathogenesis of many muscle wasting disorders, including sarcopenia. However, the contribution of elevated ROS levels to -a breakdown in neuromuscular communication and muscle atrophy remains unknown. In this study, we examined a copper zinc superoxide dismutase [CuZnSOD (Sod1)] knockout mouse (Sod1-/-), a mouse model of elevated oxidative stress that exhibits accelerated loss of muscle mass, which recapitulates many phenotypes of sarcopenia as early as 5 months of age. We found that young adult Sod1-/- mice display a considerable reduction in hind limb skeletal muscle mass and strength when compared to age-matched wild-type mice. These changes are accompanied by gross alterations in neuromuscular junction (NMJ) morphology, including reduced occupancy of the motor endplates by axons, terminal sprouting and axon thinning and irregular swelling. Surprisingly however, the average density of acetylcholine receptors in endplates is preserved. Using in vivo electromyography and ex vivo electrophysiological studies of hind limb muscles in Sod1-/- mice, we found that motor axons innervating the extensor digitorum longus (EDL) and gastrocnemius muscles release fewer synaptic vesicles upon nerve stimulation. Recordings from individually identified EDL NMJs show that reductions in neurotransmitter release are apparent in the Sod1-/- mice even when endplates are close to fully innervated. However, electrophysiological properties, such as input resistance, resting membrane potential and spontaneous neurotransmitter release kinetics (but not frequency) are similar between EDL muscles of Sod1-/- and wild-type mice. Administration of the potassium channel blocker 3,4-diaminopyridine, which broadens the presynaptic action potential, improves both neurotransmitter release and muscle strength. Together, these results suggest that ROS-associated motor nerve terminal dysfunction is a contributor to the observed muscle changes in Sod1-/- mice.
    PLoS ONE 06/2014; 9(6):e100834. DOI:10.1371/journal.pone.0100834 · 3.23 Impact Factor
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    • "In the cytoplasm, SOD1 dismutates superoxide anion radical to H2O2 that is further reduced to H2O by catalase, glutathione peroxidases or peroxiredoxins (Rhee et al., 2005). In intermembrane space (IMS), SOD1 has been suggested to play the similar protective role in handling of superoxide as in the cytosol (O’Brien et al., 2004; Aquilano et al., 2006; Klöppel et al., 2010; Fischer et al., 2011; Figure 1, reaction V). However, in this location, the scavenging systems might not be efficient enough to eliminate the H2O2 produced by dismutation. "
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    ABSTRACT: In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is recognized as one of the key elements contributing to the pathology. Mitochondria are the major source of intracellular reactive oxygen species (ROS). Increased production of ROS as well as oxidative damage of proteins and lipids have been demonstrated in many models of ALS. Moreover, these changes were also observed in tissues of ALS patients indicative of important role for oxidative stress in the disease pathology. However, the origin of oxidative stress in ALS has remained unclear. ALS linked mutant Cu/Zn-superoxide dismutase 1 (SOD1) has been shown to significantly associate with mitochondria, especially in the spinal cord. In animal models, increased recruitment of mutant SOD1 (mutSOD1) to mitochondria appears already before the disease onset, suggestive of causative role for the manifestation of pathology. Recently, substantial in vitro and in vivo evidence has accumulated demonstrating that localization of mutSOD1 to the mitochondrial intermembrane space (IMS) inevitably leads to impairment of mitochondrial functions. However, the exact mechanisms of the selectivity and toxicity have remained obscure. Here we discuss the current knowledge on the role of mutSOD1 in mitochondrial dysfunction in ALS from the novel perspective emphasizing the misregulation of dismutase activity in IMS as a major mechanism for the toxicity.
    Frontiers in Cellular Neuroscience 05/2014; 8:126. DOI:10.3389/fncel.2014.00126 · 4.29 Impact Factor
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