ALS Abstracts 1

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Curcumin binds to the pre-fibrillar aggregates of Cu/Zn superoxide dismutase (SOD1) and alters its amyloidogenic pathway resulting in reduced cytotoxicity.
            (Bhatia et al., 2015) Download
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons. Unfortunately, effective therapeutics against this disease is still not available. Almost 20% of familial ALS (fALS) is suggested to be associated with pathological deposition of superoxide dismutase (SOD1). Evidences suggest that SOD1-containing pathological inclusions in ALS exhibit amyloid like properties. An effective strategy to combat ALS may be to inhibit amyloid formation of SOD1 using small molecules. In the present study, we observed the fibrillation of one of the premature forms of SOD1 (SOD1 with reduced disulfide) in the presence of curcumin. Using ThT binding assay, AFM, TEM images and FTIR, we demonstrate that curcumin inhibits the DTT-induced fibrillation of SOD1 and favors the formation of smaller and disordered aggregates of SOD1. The enhancement in curcumin fluorescence on the addition of oligomers and pre-fibrillar aggregates of SOD1 suggests binding of these species to curcumin. Docking studies indicate that putative binding site of curcumin may be the amyloidogenic regions of SOD1. Further, there is a significant increase in SOD1 mediated toxicity in the regime of pre-fibrillar and fibrillar aggregates which is not evident in curcumin containing samples. All these data suggest that curcumin reduces toxicity by binding to the amyloidogenic regions of the species on the aggregation pathway and blocking the formation of the toxic species. Nanoparticles of curcumin with higher aqueous solubility show similar aggregation control as that of curcumin bulk. This suggests a potential role for curcumin in the treatment of ALS.

Raised nitrate concentration and low SOD activity in the CSF of sporadic ALS patients.
            (Boll et al., 2003) Download
To determine whether or not the occurrence of sporadic amyotrophic lateral sclerosis (sALS) is associated with both excess nitric oxide (NO) metabolites and decreased protective superoxide dismutase (SOD) activity in the cerebrospinal fluid (CSF), we measured nitrate concentration and SOD activity in the CSF of sALS patients and in age- and gender-matched controls. We found stable NO metabolite levels to be significantly higher and SOD activity lower in the CSF of sALS patients. In addition, SOD showed a negative correlation with motor neuron axonal damage expressed as the amplitude of motor action potentials in upper limbs. Our results provide new evidence in vivo suggesting that NO products and SOD activity play a role in oxidant/ antioxidant imbalance in sporadic ALS.

Curcumins promote monocytic gene expression related to β-amyloid and superoxide dismutase clearance.
            (Cashman et al., 2012) Download
Neurodegenerative diseases are associated with accumulation of modified proteins or peptides including amyloid-β (Aβ) in Alzheimer's disease (AD), and misfolded superoxide dismutase-1 (SOD-1) in amyotrophic lateral sclerosis (ALS). Clearance of Aβ or SOD-1 by the innate immune system may be important for controlling or preventing disease onset. Curcumins restore Aβ phagocytosis by peripheral blood mononuclear cells (PBMCs) from AD patients and Aβ clearance with upregulation of key genes including MGAT3, vitamin D receptor (VDR) and Toll-like receptors (TLRs). Certain curcumins inhibit inflammatory processes of PBMCs from ALS patients. We developed an in vitro system using human monocytes from patients and monocytic cell lines (i.e. U-937, THP-1) for evaluating curcuminoid potency of innate immune cell stimulation. Bisdemethoxycurcumin and certain analogs potentiated MGAT3,VDR and TLR gene expression 3- to 300-fold in U-937 cells. The effect of curcumins on inflammation in monocytes from patients with ALS was examined. Recursive medicinal chemistry was applied to identify compounds that stimulate the innate immune system for use in the clearance of Aβ in AD and the reversal of neuroinflammation and defective SOD-1 accumulation in ALS.

Protection by dietary zinc in ALS mutant G93A SOD transgenic mice.
            (Ermilova et al., 2005) Download
Mutations to the copper, zinc superoxide dismutase (SOD) gene are responsible for 2-3% of amyotrophic lateral sclerosis (ALS) cases. These mutations result in the protein having a reduced affinity for zinc. SOD becomes toxic to motor neurons when zinc is missing from its active site. Recently, high dosages of zinc (75 and 375 mg/kg/day) have been paradoxically reported to increase the death of G93A-mutant SOD transgenic mice [G.J. Groeneveld, J. de Leeuw van Weenen, F.L. van Muiswinkel, H. Veldman, J.H. Veldink, J.H. Wokke, P.R. Bar, L.H. van den Berg, Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis, Neurosci. Lett. 352 (2003) 175-178]. In contrast, we have found that moderate supplementation of zinc (approximately 12 mg/kg/day) delayed death in G93A-mutant SOD mice by 11 days compared to mice on a zinc-deficient diet. Supplementing zinc with even 18 mg/kg/day resulted in a more rapid death of some mice, consistent with the results of Groenevelt et al. However, large amounts of zinc competitively inhibit copper absorption, which inhibits the copper-dependent ceruloplasmin, and can cause a lethal anemia. We found that supplementing the 18 mg/kg/day dosage of zinc with 0.3 mg/kg/day of copper prevented the early death from zinc treatment alone. These data support a role for moderate levels of dietary zinc potentially protecting against the toxicity of ALS-associated SOD and the protection does not result from depleting copper.

Vitamin D(3) at 50x AI attenuates the decline in paw grip endurance, but not disease outcomes, in the G93A mouse model of ALS, and is toxic in females.
            (Gianforcaro et al., 2013) Download
BACKGROUND:  We previously demonstrated that dietary vitamin D(3) at 10x the adequate intake (AI) attenuates the decline in functional capacity in the G93A mouse model of ALS. We hypothesized that higher doses would elicit more robust changes in functional and disease outcomes. OBJECTIVE:  To determine the effects of dietary vitamin D(3) at 50xAI on functional outcomes (motor performance, paw grip endurance) and disease severity (clinical score), as well as disease onset, disease progression and lifespan in the transgenic G93A mouse model of ALS. METHODS:  Starting at age 25 d, 100 G93A mice (55 M, 45 F) were provided ad libitum with either an adequate (AI; 1 IU D(3)/g feed) or high (HiD; 50 IU D(3)/g feed) vitamin D(3) diet. RESULTS:  HiD females consumed 9% less food corrected for body weight vs. AI females (P = 0.010). HiD mice had a 12% greater paw grip endurance over time between age 60-141 d (P = 0.015), and a 37% greater score during disease progression (P = 0.042) vs. AI mice. Although HiD females had a non-significant 31% greater CS prior to disease onset vs. AI females, they exhibited a significant 20% greater paw grip endurance AUC (P = 0.020) when corrected for clinical score. CONCLUSION:  Dietary D(3) supplementation at 50x the adequate intake attenuated the decline in paw grip endurance, but did not influence age at disease onset, hindlimb paralysis or endpoint in the transgenic G93A mouse model of ALS. Furthermore, females may have reached the threshold for vitamin D(3) toxicity as evidence by reduced food intake and greater disease severity prior to disease onset.

Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis.
            (Groeneveld et al., 2003) Download
Transgenic mice overexpressing the human mutated form (G93A) of Cu,Zn-superoxide dismutase (mSOD1) develop motor neuron degeneration resembling amyotrophic lateral sclerosis. In vitro studies have shown that mSOD1-induced, reactive oxygen species-mediated apoptosis of motor neurons depends on the presence of copper and the relative absence of zinc. Oral intake of zinc sulphate induces the expression of metallothioneins, enzymes that decrease oxidative stress, and leads to higher serum zinc, and lower copper levels. We therefore tested the effect of chronic oral administration of zinc sulfate (0.075 and 0.375 g/kg) on disease onset and survival of mSOD1 transgenic mice. We observed that zinc sulfate, rather than prolonging survival, decreased survival. We conclude that zinc sulfate amplifies the mSOD1 transgenic mouse phenotype. This finding may shed more light on the role of zinc in mSOD1-mediated toxicity.

Enhancing NAD+ Salvage Pathway Reverts the Toxicity of Primary Astrocytes Expressing Amyotrophic Lateral Sclerosis-linked Mutant Superoxide Dismutase 1 (SOD1).
            (Harlan et al., 2016) Download
Nicotinamide adenine dinucleotide (NAD(+)) participates in redox reactions and NAD(+)-dependent signaling pathways. Although the redox reactions are critical for efficient mitochondrial metabolism, they are not accompanied by any net consumption of the nucleotide. On the contrary, NAD(+)-dependent signaling processes lead to its degradation. Three distinct families of enzymes consume NAD(+) as substrate: poly(ADP-ribose) polymerases, ADP-ribosyl cyclases (CD38 and CD157), and sirtuins (SIRT1-7). Because all of the above enzymes generate nicotinamide as a byproduct, mammalian cells have evolved an NAD(+) salvage pathway capable of resynthesizing NAD(+) from nicotinamide. Overexpression of the rate-limiting enzyme in this pathway, nicotinamide phosphoribosyltransferase, increases total and mitochondrial NAD(+) levels in astrocytes. Moreover, targeting nicotinamide phosphoribosyltransferase to the mitochondria also enhances NAD(+) salvage pathway in astrocytes. Supplementation with the NAD(+) precursors nicotinamide mononucleotide and nicotinamide riboside also increases NAD(+) levels in astrocytes. Amyotrophic lateral sclerosis (ALS) is caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Superoxide dismutase 1 (SOD1) mutations account for up to 20% of familial ALS and 1-2% of apparently sporadic ALS cases. Primary astrocytes isolated from mutant human superoxide dismutase 1-overexpressing mice as well as human post-mortem ALS spinal cord-derived astrocytes induce motor neuron death in co-culture. Increasing total and mitochondrial NAD(+) content in ALS astrocytes increases oxidative stress resistance and reverts their toxicity toward co-cultured motor neurons. Taken together, our results suggest that enhancing the NAD(+) salvage pathway in astrocytes could be a potential therapeutic target to prevent astrocyte-mediated motor neuron death in ALS.

Metal-deficient SOD1 in amyotrophic lateral sclerosis.
            (Hilton et al., 2015) Download
Mutations to the ubiquitous antioxidant enzyme Cu/Zn superoxide dismutase (SOD1) were the first established genetic cause of the fatal, adult-onset neurodegenerative disease amyotrophic lateral sclerosis (ALS). It is widely accepted that these mutations do not cause ALS via a loss of antioxidant function, but elucidating the alternate toxic gain of function has proven to be elusive. Under physiological conditions, SOD1 binds one copper ion and one zinc ion per monomer to form a highly stable and functional homodimer, but there is now ample evidence to indicate aberrant persistence of SOD1 in an intermediate metal-deficient state may contribute to the protein's involvement in ALS. This review briefly discusses some of the data to support a role for metal-deficient SOD1 in the development of ALS and some of the outcomes from drug development studies that have aimed to modify the symptoms of ALS by targeting the metal state of SOD1. The implications for the metal state of SOD1 in cases of sporadic ALS that do not involve mutant SOD1 are also discussed.

Cytotoxicity of superoxide dismutase 1 in cultured cells is linked to Zn2+ chelation.
            (Johansson et al., 2012) Download
Neurodegeneration in protein-misfolding disease is generally assigned to toxic function of small, soluble protein aggregates. Largely, these assignments are based on observations of cultured neural cells where the suspect protein material is titrated directly into the growth medium. In the present study, we use this approach to shed light on the cytotoxic action of the metalloenzyme Cu/Zn superoxide dismutase 1 (SOD1), associated with misfolding and aggregation in amyotrophic lateral sclerosis (ALS). The results show, somewhat unexpectedly, that the toxic species of SOD1 in this type of experimental setting is not an aggregate, as typically observed for proteins implicated in other neuro-degenerative diseases, but the folded and fully soluble apo protein. Moreover, we demonstrate that the toxic action of apoSOD1 relies on the protein's ability to chelate Zn(2+) ions from the growth medium. The decreased cell viability that accompanies this extraction is presumably based on disturbed Zn(2+) homeostasis. Consistently, mutations that cause global unfolding of the apoSOD1 molecule or otherwise reduce its Zn(2+) affinity abolish completely the cytotoxic response. So does the addition of surplus Zn(2+). Taken together, these observations point at a case where the toxic response of cultured cells might not be related to human pathology but stems from the intrinsic limitations of a simplified cell model. There are several ways proteins can kill cultured neural cells but all of these need not to be relevant for neurodegenerative disease.

Pyruvate protects motor neurons expressing mutant superoxide dismutase 1 against copper toxicity.
            (Kim et al., 2005) Download
Mutations in the copper/zinc superoxide dismutase (SOD1) gene are known to be responsible for familial amyotrophic lateral sclerosis. Alteration of metal binding properties of mutant SOD1 has been proposed to play a role in the pathogenesis of amyotrophic lateral sclerosis. We investigated the toxic effects of excess extracellular copper on motor neuronal cells expressing human mutant SOD1 (G93A), and evaluated the neuroprotective effects of energy metabolism intermediates or cofactors. Motoneuron-neuroblastoma hybrid (VSC 4.1) cells expressing mutant SOD1, when treated with copper chloride, showed reduced viability and increased levels of endogenous peroxides. Moreover, this copper-induced toxicity was attenuated by a free radical scavenger, a caspase inhibitor, or a calpain inhibitor. Of the energy metabolism intermediates examined, pyruvate significantly reduced the death and production of reactive oxygen species in cells expressing mutant SOD1. Our data suggest that pyruvate could be of therapeutic value in some forms of familial amyotrophic lateral sclerosis.

L-carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis
            (Kira et al., 2006) Download
Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by progressive degeneration of motor neurons in the spinal cord and motor cortex. Although the etiology of ALS remains unknown, a mutation of the gene encoding Cu,Zn-superoxide dismutase (SOD1) has been reported in 20% of familial cases of ALS (FALS). Transgenic mice that overexpress a mutated human SOD1 exhibit a phenotype and pathology similar to those observed in patients with FALS. Mitochondrial abnormality has been reported in patients with ALS and in animal models of FALS. We recently reported that L-carnitine, an essential cofactor for the beta-oxidation of long-chain fatty acids, effectively inhibits various types of mitochondrial injury and apoptosis both in vitro and in vivo. The present study demonstrates that oral administration of L-carnitine prior to disease onset significantly delayed the onset of signs of disease (log-rank P=0.0008), delayed deterioration of motor activity, and extended life span (log-rank P=0.0001) in transgenic mice carrying a human SOD1 gene with a G93A mutation (Tg). More importantly, subcutaneous injection of L-carnitine increased the life span of Tg mice (46% increase in male, 60% increase in female) even when given after the appearance of signs of disease.

Dietary Vitamin D3 Restriction Exacerbates Disease Pathophysiology in the Spinal Cord of the G93A Mouse Model of Amyotrophic Lateral Sclerosis.
            (Moghimi et al., 2015) Download
BACKGROUND:  Dietary vitamin D3 (D3) restriction reduces paw grip endurance and motor performance in G93A mice, and increases inflammation and apoptosis in the quadríceps of females. ALS, a neuromuscular disease, causes progressive degeneration of motor neurons in the brain and spinal cord. OBJECTIVE:  We analyzed the spinal cords of G93A mice following dietary D3 restriction at 2.5% the adequate intake (AI) for oxidative damage (4-HNE, 3-NY), antioxidant enzymes (SOD2, catalase, GPx1), inflammation (TNF-α, IL-6, IL-10), apoptosis (bax/bcl-2 ratio, cleaved/pro-caspase 3 ratio), neurotrophic factor (GDNF) and neuron count (ChAT, SMI-36/SMI-32 ratio). METHODS:  Beginning at age 25 d, 42 G93A mice were provided food ad libitum with either adequate (AI;1 IU D3/g feed; 12 M, 11 F) or deficient (DEF; 0.025 IU D3/g feed; 10 M, 9 F) D3. At age 113 d, the spinal cords were analyzed for protein content. Differences were considered significant at P ≤ 0.10, since this was a pilot study. RESULTS:  DEF mice had 16% higher 4-HNE (P = 0.056), 12% higher GPx1 (P = 0.057) and 23% higher Bax/Bcl2 ratio (P = 0.076) vs. AI. DEF females had 29% higher GPx1 (P = 0.001) and 22% higher IL-6 (P = 0.077) vs. AI females. DEF males had 23% higher 4-HNE (P = 0.066) and 18% lower SOD2 (P = 0.034) vs. AI males. DEF males had 27% lower SOD2 (P = 0.004), 17% lower GPx1 (P = 0.070), 29% lower IL-6 (P = 0.023) and 22% lower ChAT (P = 0.082) vs. DEF females. CONCLUSION:  D3 deficiency exacerbates disease pathophysiology in the spinal cord of G93A mice, the exact mechanisms are sex-specific. This is in accord with our previous results in the quadriceps, as well as functional and disease outcomes.

Rosmarinic Acid Alleviates Neurological Symptoms in the G93A-SOD1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.
            (Seo et al., 2015) Download
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons in the brain and spinal cord, resulting in paralysis of voluntary skeletal muscles and eventually death, usually within 2~3 years of symptom onset. The pathophysiology mechanism underlying ALS is not yet clearly understood. Moreover the available medication for treating ALS, riluzole, only modestly improves neurological symptoms and increases survival by a few months. Therefore, improved therapeutic strategies are urgently needed. In the present study, we investigated whether rosmarinic acid has a therapeutic potential to alleviate neurological deterioration in the G93A-SOD1 transgenic mouse model of ALS. Treatment of G93A-SOD1 transgenic mice with rosmarinic acid from 7 weeks of age at the dose of 400 mg/kg/day significantly extended survival, and relieved motor function deficits. Specifically, disease onset and symptom progression were delayed by more than one month. These symptomatic improvements were correlated with decreased oxidative stress and reduced neuronal loss in the ventral horns of G93A-SOD1 mice. These results support that rosmarinic acid is a potentially useful supplement for relieving ALS symptoms.

Effect of rosmarinic acid in motor dysfunction and life span in a mouse model of familial amyotrophic lateral sclerosis
            (Shimojo et al., 2009) Download
Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disease affecting motor neurons. About 2% of patients with the disease are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). The purpose of this study is to assess the effect of rosemary extract and its major constituents, rosmarinic acid (RA) and carnosic acid (CA), in human SOD1 G93A transgenic mice, which are well-established mouse models for ALS. The present study demonstrates that intraperitoneal administration of rosemary extract or RA from the presymptomatic stage significantly delayed motor dysfunction in paw grip endurance tests, attenuated the degeneration of motor neurons, and extended the life span of ALS model mice. In addition, RA administration significantly improved the clinical score and suppressed body weight loss compared with a vehicle-treated group. In conclusion, this study provides the first report that rosemary extract and, especially, RA have preventive effects in the mouse model of ALS.

Homocysteine induces oxidative cytotoxicity in Cu,Zn-superoxide dismutase mutant motor neuronal cell
            (Sung et al., 2002) Download
Mutations in human Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism of late-onset disease manifestation despite the innate mutation has no clear explanation. The relationship between homocysteine (HC) and amyotrophic lateral sclerosis (ALS) has not been investigated, in spite of the similarity in their pathogenesis. We investigated the effect of HC on the motor neuronal cell-line transfected with SOD1 of either wild-type or one of two mutant forms (G93A and A4V). In the MTT assay, HC induced significant cytotoxicity in A4V, but not in G93A, as compared with wild-type, even at the physiological concentration of 10 microM. This HC-induced cytotoxicity was inhibited by the antioxidant trolox and the Cu (I) chelator bathocuproinedisulfonate. Here we show that the vulnerability of the A4 V mutant involves the cytotoxic copper-mediated pathway, and that HC may be a lifelong precipitating factor in some forms of FALS, suggesting the possible treatment modality with vitamin supplements.

Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations.
            (Tokuda and Furukawa, 2016) Download
Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease affecting both upper and lower motor neurons, and currently, there is no cure or effective treatment. Mutations in a gene encoding a ubiquitous antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1), have been first identified as a cause of familial forms of ALS. It is widely accepted that mutant SOD1 proteins cause the disease through a gain in toxicity but not through a loss of its physiological function. SOD1 is a major copper-binding protein and regulates copper homeostasis in the cell; therefore, a toxicity of mutant SOD1 could arise from the disruption of copper homeostasis. In this review, we will briefly review recent studies implying roles of copper homeostasis in the pathogenesis of SOD1-ALS and highlight the therapeutic interventions focusing on pharmacological as well as genetic regulations of copper homeostasis to modify the pathological process in SOD1-ALS.


 

A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis.
            (Trumbull and Beckman, 2009) Download
In the 16 years since mutations to copper, zinc superoxide dismutase (SOD1) were first linked to familial amyotrophic lateral sclerosis (ALS), a multitude of apparently contradictory results have prevented any general consensus to emerge about the mechanism of toxicity. A decade ago, we showed that the loss of zinc from SOD1 results in the remaining copper in SOD1 to become extremely toxic to motor neurons in culture by a mechanism requiring nitric oxide. The loss of zinc causes SOD1 to become more accessible, more redox reactive, and a better catalyst of tyrosine nitration. Although SOD1 mutant proteins have a modestly reduced affinity for zinc, wild-type SOD1 can be induced to lose zinc by dialysis at slightly acidic pH. Our zinc-deficient hypothesis offers a compelling explanation for how mutant SOD1s have an increased propensity to become selectively toxic to motor neurons and also explains how wild-type SOD1 can be toxic in nonfamilial ALS patients. One critical prediction is that a therapeutic agent directed at zinc-deficient mutant SOD1 could be even more effective in treating sporadic ALS patients. Although transgenic mice experiments have yielded contradictory evidence to the zinc-deficient hypothesis, we will review more recent studies that support a role for copper in ALS. A more careful examination of the role of copper and zinc binding to SOD1 may help counter the growing disillusion in the ALS field about understanding the pathological role of SOD1.


 

References

Bhatia, NK, et al. (2015), ‘Curcumin binds to the pre-fibrillar aggregates of Cu/Zn superoxide dismutase (SOD1) and alters its amyloidogenic pathway resulting in reduced cytotoxicity.’, Biochim Biophys Acta, 1854 (5), 426-36. PubMed: 25666897
Boll, MC, et al. (2003), ‘Raised nitrate concentration and low SOD activity in the CSF of sporadic ALS patients.’, Neurochem Res, 28 (5), 699-703. PubMed: 12716019
Cashman, JR, et al. (2012), ‘Curcumins promote monocytic gene expression related to β-amyloid and superoxide dismutase clearance.’, Neurodegener Dis, 10 (1-4), 274-76. PubMed: 22156608
Ermilova, IP, et al. (2005), ‘Protection by dietary zinc in ALS mutant G93A SOD transgenic mice.’, Neurosci Lett, 379 (1), 42-46. PubMed: 15814196
Gianforcaro, A, JA Solomon, and MJ Hamadeh (2013), ‘Vitamin D(3) at 50x AI attenuates the decline in paw grip endurance, but not disease outcomes, in the G93A mouse model of ALS, and is toxic in females.’, PLoS One, 8 (2), e30243. PubMed: 23405058
Groeneveld, GJ, et al. (2003), ‘Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis.’, Neurosci Lett, 352 (3), 175-78. PubMed: 14625013
Harlan, BA, et al. (2016), ‘Enhancing NAD+ Salvage Pathway Reverts the Toxicity of Primary Astrocytes Expressing Amyotrophic Lateral Sclerosis-linked Mutant Superoxide Dismutase 1 (SOD1).’, J Biol Chem, 291 (20), 10836-46. PubMed: 27002158
Hilton, JB, AR White, and PJ Crouch (2015), ‘Metal-deficient SOD1 in amyotrophic lateral sclerosis.’, J Mol Med (Berl), 93 (5), 481-87. PubMed: 25754173
Johansson, AS, et al. (2012), ‘Cytotoxicity of superoxide dismutase 1 in cultured cells is linked to Zn2+ chelation.’, PLoS One, 7 (4), e36104. PubMed: 22558346
Kim, HJ, et al. (2005), ‘Pyruvate protects motor neurons expressing mutant superoxide dismutase 1 against copper toxicity.’, Neuroreport, 16 (6), 585-89. PubMed: 15812313
Kira, Y., et al. (2006), ‘L-carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis’, Brain Res, 1070 (1), 206-14. PubMed: 16412993
Moghimi, E, et al. (2015), ‘Dietary Vitamin D3 Restriction Exacerbates Disease Pathophysiology in the Spinal Cord of the G93A Mouse Model of Amyotrophic Lateral Sclerosis.’, PLoS One, 10 (5), e0126355. PubMed: 26020962
Seo, JS, et al. (2015), ‘Rosmarinic Acid Alleviates Neurological Symptoms in the G93A-SOD1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.’, Exp Neurobiol, 24 (4), 341-50. PubMed: 26713081
Shimojo, Y., et al. (2009), ‘Effect of rosmarinic acid in motor dysfunction and life span in a mouse model of familial amyotrophic lateral sclerosis’, J Neurosci Res, 88 (4), 896-904. PubMed: 19798750
Sung, J. J., et al. (2002), ‘Homocysteine induces oxidative cytotoxicity in Cu,Zn-superoxide dismutase mutant motor neuronal cell’, Neuroreport, 13 (4), 377-81. PubMed: 11930144
Tokuda, E and Y Furukawa (2016), ‘Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations.’, Int J Mol Sci, 17 (5), PubMed: 27136532
Trumbull, KA and JS Beckman (2009), ‘A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis.’, Antioxid Redox Signal, 11 (7), 1627-39. PubMed: 19309264