Superoxide Dismutase 1 Gene Mutation Research Articles

Somatosensory pathway dysfunction in patients with amyotrophic lateral sclerosis in a completely locked-in state

ObjectiveTo investigate somatosensory pathway function in patients with amyotrophic lateral sclerosis (ALS) dependent on invasive ventilation and in a completely locked-in state (CLIS). MethodsWe examined median nerve somatosensory evoked potentials (SEPs) in 17 ALS patients in a CLIS, including 11 patients with sporadic ALS, one with familial ALS with genes not examined, four with a Cu/Zn superoxide-dismutase-1 (SOD1) gene variant (Val118Leu, Gly93Ser, Cys146Arg), and one with a fused-in-sarcoma gene variant (P525L). We evaluated N9, N13, N20 and P25, and central conduction time (CCT); the data were compared with those of 73 healthy controls. ResultsN20 and N13 were abolished in 12 and 10 patients, and their latencies was prolonged in four and three patients, respectively. The CCT was prolonged in five patients with measurable N13 and N20. Two patients with SOD1 gene mutations had absent or slightly visible N9. Compared to the CCT and latencies and amplitudes of N13 and N20 in the controls, those in the patient cohort were significantly abnormal. ConclusionsThe central somatosensory pathway is severely involved in patients with ALS in a CLIS. SignificanceOur findings suggest that median nerve SEP cannot be utilized for communication in patients with ALS in a CLIS.

Mutation-specific metabolic profiles in presymptomatic amyotrophic lateral sclerosis.

Growing evidence shows that ALS patients feature a disturbed energy metabolism. However, these features have rarely been investigated in the presymptomatic stage. A total of 60 presymptomatic ALS mutation carriers and 70 age- and gender-matched controls (non-mutation carriers from the same families) were recruited. All subjects underwent assessments of their metabolic profiles under fasting conditions at enrollment, including body mass index (BMI), blood pressure and serum levels of blood glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein. All mutations combined, no differences between presymptomatic ALS gene carriers and controls were found. From a cardiovascular point of view, presymptomatic chromosome 9 open reading frame 72 (C9ORF72) gene carriers showed lower cardiovascular risk profiles compared to healthy controls, including lower BMI (median 22.9, interquartile range [IQR] 20.6-26.1 kg/m2 vs. 24.9, IQR 22.7-30.5 kg/m2 ; p=0.007), lower systolic blood pressure (120, IQR 110-130 mmHg vs. 128, IQR 120-140 mmHg; p=0.02), lower fasting serum glucose (89.0, IQR 85.0-97.0 mg/dl vs. 96.0, IQR 89.3-102.0 mg/dl; p=0.005) and higher HDL (1.6, IQR 1.3-1.8 mmol/l vs. 1.2, IQR 1.0-1.4 mmol/l; p=0.04). However, presymptomatic superoxide dismutase 1 (SOD1) gene mutation carriers showed higher cardiovascular risk profiles compared to healthy controls, including higher BMI (28.0,IQR 26.1-31.5 kg/m2 vs. 24.9, IQR 22.7-30.5 kg/m2 ; p=0.02), higher fasting serum glucose (100.0, IQR 94.0-117.0 mg/dl vs. 96.0, IQR 89.3-102.0 mg/dl; p=0.04) and lower HDL (1.2, IQR 1.0-1.4 mmol/l vs. 1.4, IQR 1.2-1.7 mmol/l; p=0.01). These features were most prominent in patients carrying SOD1 gene mutations associated with slow disease progression. This study identified distinct metabolic profiles in presymptomatic ALS gene carriers, which might be associated with disease progression in the symptomatic phase.

Integrative Analysis of Motor Neuron and Microglial Transcriptomes from SOD1G93A Mice Models Uncover Potential Drug Treatments for ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neurons that mainly affects the motor cortex, brainstem, and spinal cord. Under disease conditions, microglia could possess two distinct profiles, M1 (toxic) and M2 (protective), with the M2 profile observed at disease onset. SOD1 (superoxide dismutase 1) gene mutations account for up to 20% of familial ALS cases. Comparative gene expression differences in M2-protective (early) stage SOD1G93A microglia and age-matched SOD1G93A motor neurons are poorly understood. We evaluated the differential gene expression profiles in SOD1G93A microglia and SOD1G93A motor neurons utilizing publicly available transcriptomics data and bioinformatics analyses, constructed biomolecular networks around them, and identified gene clusters as potential drug targets. Following a drug repositioning strategy, 5 small compounds (belinostat, auranofin, BRD-K78930611, AZD-8055, and COT-10b) were repositioned as potential ALS therapeutic candidates that mimic the protective state of microglia and reverse the toxic state of motor neurons. We anticipate that this study will provide new insights into the ALS pathophysiology linking the M2 state of microglia and drug repositioning.

Dysregulations of Expression of Genes of the Ubiquitin/SUMO Pathways in an In Vitro Model of Amyotrophic Lateral Sclerosis Combining Oxidative Stress and SOD1 Gene Mutation.

Protein aggregates in affected motor neurons are a hallmark of amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to their formation remain incompletely understood. Oxidative stress associated with age, the major risk factor in ALS, contributes to this neurodegeneration in ALS. We show that several genes coding for enzymes of the ubiquitin and small ubiquitin-related modifier (SUMO) pathways exhibit altered expression in motor neuronal cells exposed to oxidative stress, such as the CCNF gene mutated in ALS patients. Eleven of these genes were further studied in conditions combining oxidative stress and the expression of an ALS related mutant of the superoxide dismutase 1 (SOD1) gene. We observed a combined effect of these two environmental and genetic factors on the expression of genes, such as Uhrf2, Rbx1, Kdm2b, Ube2d2, Xaf1, and Senp1. Overall, we identified dysregulations in the expression of enzymes of the ubiquitin and SUMO pathways that may be of interest to better understand the pathophysiology of ALS and to protect motor neurons from oxidative stress and genetic alterations.

Long-term observation of benign familial amyotrophic lateral sclerosis (FALS)with a h46r mutation in superoxide dismutase1 gene(SOD1)

Background: Background: FALS with a His46Arg(H46R) substitution of SOD1(ALS1 H46R) shows slow progression without bulbar and respiratory muscle weakness.

Overexpression of Human SOD1 Leads to Discrete Defects in the Cerebellar Architecture in the Mouse.

The human superoxide dismutase 1 (SOD1) gene is responsible for neutralizing supercharged oxygen radicals within the cell. Mutation in SOD1 gene causes amyotrophic lateral sclerosis (ALS). Recent studies have shown involvement of the cerebellum in ALS, although the cerebellar contribution in SOD1 transgenic mice remains unclear. Using immunohistopathology, we investigated the Purkinje cell phenotype in the vermis of the SOD1 transgenic mice cerebellum. Calbindin 1 (Calb1) and three well-known zone and stripe markers, zebrin II, HSP25, and PLCβ4 have been used to explore possible alteration in zone and stripe. Here we show that Calb1 expression is significantly reduced in a subset of the Purkinje cells that is almost aligned with the cerebellar zones and stripes pattern. The Purkinje cells of SOD1 transgenic mice display a pattern of Calb1 down-regulation, which seems to proceed to Purkinje cell degeneration as the mice age. The onset of Calb1 down-regulation in Purkinje cells begins from the central zone and continues into the nodular zone, however it has not been observed in the anterior and posterior zones. In a subgroup of SOD1 transgenic mice in which gait unsteadiness was apparent, down-regulation of Calb1 is seen in a subset of PLCβ4+ Purkinje cells in the anterior zone. These observations suggest that the Calb1− subset of Purkinje cells in the anterior zone, which receives somatosensory input, causes unsteady gait. Our data suggest that human SOD1 overexpression leads to Calb1 down-regulation in the zone and strip pattern and raise the question of whether SOD1 overexpression leads to Purkinje cells degeneration.

Familial amyotrophic lateral sclerosis with an I104F mutation in the SOD1 gene: Multisystem degeneration with neurofilamentous aggregates and SOD1 inclusions

We previously reported familial amyotrophic lateral sclerosis (FALS) of 11years duration in a 57-year-old woman, who received artificial ventilation for 5years prior to death and exhibited widespread multisystem degeneration and neurofilamentous aggregates, so-called conglomerate inclusions (CIs). In the present study, we re-evaluated this autopsied patient (proband) with further immunohistochemical observation as well as mutational analysis of the superoxide dismutase 1 (SOD1) gene. A review of the clinical features of the proband's family revealed five affected members (including the proband) over two successive generations who showed marked variability in clinical presentation, such as the age at onset. The proband was found to harbor a heterozygous missense mutation in exon 4 (I104F) of the SOD1 gene. In the brain and spinal cord, SOD1-positive neuronal cytoplasmic inclusions (NCIs) were found to be more widely distributed than CIs, the latter being weakly positive for SOD1. No Lewy body-like hyaline inclusions were found. This is considered to be the first description of an autopsy case of FALS with an I104F SOD1 gene mutation, suggesting that combination of marked intra-familial clinical variability and multisystem degeneration with occurrence of CIs and SOD1-positive NCIs is a characteristic feature of FALS with this SOD1 gene mutation.

Amyotrophic lateral sclerosis models derived from human embryonic stem cells with different superoxide dismutase 1 mutations exhibit differential drug responses

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron (MN) disease. The gene encoding superoxide dismutase 1 (SOD1) is a causative element of familial ALS. Animal ALS models involving SOD1 gene mutations are widely used to study the underlying mechanisms of disease and facilitate drug discovery. Unfortunately, most drug candidates have failed in clinical trials, potentially due to species differences among rodents and humans. It is unclear, however, whether there are different responses to drugs among the causative genes of ALS or their associated mutations. In this study, to evaluate different SOD1 mutations, we generated SOD1-ALS models derived from human embryonic stem cells with identical genetic backgrounds, except for the overexpression of mutant variants of SOD1. The overexpression of mutant SOD1 did not affect pluripotency or MN differentiation. However, mutation-dependent reductions in neurite length were observed in MNs. Moreover, experiments investigating the effects of specific compounds revealed that each ALS model displayed different responses with respect to MN neurite length. These results suggest that SOD1 mutations could be classified based the response of MNs to drug treatment. This classification could be useful for the development of mutant-specific strategies for drug discovery and clinical trials.

MCP-1/CCR2 signaling-mediated astrocytosis is accelerated in a transgenic mouse model of SOD1-mutated familial ALS

BackgroundEmerging evidence suggests that innate immunity and increased oxidative stress contribute to pathomechanisms in amyotrophic lateral sclerosis (ALS). The aim of the present study was to verify the involvement of monocyte chemoattractant protein-1 (MCP-1) and its specific CC chemokine receptor 2 (CCR2) in the disease progression of ALS. We here demonstrate the expression state of MCP-1 and CCR2 in lumbar spinal cords of mice overexpressing a transgene for G93A mutant human superoxide dismutase 1 (SOD1) (ALS mice) as a mouse model of ALS as well as the involvement of MCP-1/CCR2-mediated signaling in behavior of cultured astrocytes derived from those mice.ResultsQuantitative polymerase chain reaction analysis revealed that MCP-1 and CCR2 mRNA levels were significantly higher in ALS mice than those in nontransgenic littermates (control mice) at the presymptomatic stage. Immunoblot analysis disclosed a significantly higher CCR2/β-actin optical density ratio in the postsymptomatic ALS mouse group than those in the age-matched control mouse group. Immunohistochemically, MCP-1 determinants were mainly localized in motor neurons, while CCR2 determinants were exclusively localized in reactive astrocytes. Primary cultures of astrocytes derived from ALS mice showed a significant increase in proliferation activity under recombinant murine MCP-1 stimuli as compared to those from control mice.ConclusionsOur results provide in vivo and in vitro evidence that MCP-1 stimulates astrocytes via CCR2 to induce astrocytosis in ALS with SOD1 gene mutation. Thus, it is likely that MCP-1/CCR2-mediated sigaling is involved in the disease progression of ALS.

Distinctive clinicopathological features of 2 large families with amyotrophic lateral sclerosis having L106V mutation in SOD1 gene

A clinicopathological study of 2 families with familial amyotrophic lateral sclerosis was previously reported [1]. The present study continues to investigate these families, with detailed clinical, genetic, and neuropathological studies performed on 24 patients, including 5 autopsy cases of the families. A point mutation at codon 106 (L106V) in the copper/zinc superoxide dismutase-1 (SOD1) gene was identified in the families. Average age at onset was 52.0±9.4years, and initial symptoms were weakness and atrophy in the distal muscles of the lower extremities in most patients. Half of the patients showed neurogenic bladder (overactive bladder) and sensory impairment. The neurophysiological study showed peripheral/central conduction delay. Neuropathological examination revealed severe motor neuron loss with many bizarre reactive astrocytes in the spinal anterior horn. SOD1-immunopositive Lewy body-like hyaline inclusions and aggregation of neurofilaments were observed in the surviving anterior horn cells. Degeneration of the corticospinal tract was relatively minor. In addition, slight but diffuse gliosis was identified in the hypothalamus and medial nucleus of thalamus. Neurogenic bladder, sensory impairment, and degeneration of the hypothalamus and thalamus might be specific features in patients with familial amyotrophic lateral sclerosis with L106V mutation in the SOD1 gene.

Magnetic resonance imaging of pathological processes in rodent models of amyotrophic lateral sclerosis

Non-human models of neurodegenerative diseases have potential for the identification of key pathways in pathogenesis and for the more rapid assessment of therapeutic candidates. While there are legitimate concerns about the physiological differences between the rodent and human motor systems, mice expressing the 'G93A' superoxide dismutase-1 gene mutation are a predictable and robustly-characterized model for amyotrophic lateral sclerosis (ALS). This model has provided evidence for an important role of inflammatory processes during the pre-clinical phase, a stage currently inaccessible for human study in what is largely a sporadic disease. While magnetic resonance imaging is now an established and leading modality for the identification of ALS biomarkers in humans, it can also be increasingly applied to rodent models to probe structural, functional and biochemical changes throughout the course of the disease, with additional potential to generate surrogate markers for the efficacy of therapeutic interventions. Targeted MRI contrast agents, through tagging of various cell types and even individual molecules, will deliver an era of in vivo molecular neuroimaging, with greater specificity for the most relevant pathological processes. These are potentially important steps towards the ultimate goal of human therapeutic translation.

Vocal cord paralysis and rapid progressive motor neuron disease by the I113F mutation in SOD1 gene

Familial cases of amyotrophic lateral sclerosis are most frequently caused by mutation in the superoxide dismutase-1 (SOD1) gene. We report a heterozygous I113F mutation in a patient with familial ALS characterized by early and predominant bilateral vocal cord paralysis followed by descending spinal cord paresis. Modelling of the mutant SOD1 showed an alteration of the protein secondary structure leading to impaired strength of the dimer interface. This may result in a failure of the protein folding and subsequently generation of toxic intracellular aggregates, suggesting a pathogenic role for the mutation.

FALS with Gly72Ser mutation in SOD1 gene: Report of a family including the first autopsy case

Clinical information on familial amyotrophic lateral sclerosis (FALS) with Gly72Ser mutation in the Cu/Zn superoxide dismutase-1 (SOD1) gene has been limited and autopsy findings remain to be clarified. We describe one Japanese family with ALS carrying Gly72Ser mutation in the SOD1 gene, in which autopsy was performed on one affected member. The autopsied female patient developed muscle weakness of the left thigh at age 66 and showed transient upper motor neuron signs. She died of respiratory failure 13 months after onset without artificial respiratory support. There were no symptoms suggesting bladder or rectal dysfunction throughout the clinical course. Her brother with ALS was shown to have Gly72Ser mutation in the SOD1 gene. Histopathologically, motor neurons were markedly decreased throughout the whole spinal cord, whereas corticospinal tract involvement was very mild and was demonstrated only by CD68 immunohistochemistry. Degeneration was evident in the posterior funiculus, Clarke's nucleus, posterior cerebellar tract, and Onuf's nucleus. Neuronal hyaline inclusions were rarely observed in the neurons of the spinal cord anterior horn including Onuf's nucleus, and were immunoreactive for SOD1. To date, neuron loss in Onuf's nucleus has hardly been seen in ALS, except in the patients showing prolonged disease duration with artificial respiratory support. Involvement of Onuf's nucleus may be a characteristic pathological feature in FALS with Gly72Ser mutation in the SOD1 gene.

Award-C High frequency oscillations during epileptic spikes: automatic and visual analysis

Objective: Diffusion tensor imaging (DTI) recently identified structural abnormalities of corticomotoneurons in asymptomatic copper/zinc superoxide-dismutase-1 (SOD-1) gene mutation carriers. The potential existence of longstanding corticomotoneuronal dysfunction would clearly have consequences for the medical management of asymptomatic SOD-1 mutation carriers. To clarify this unexpected finding, DTI techniques were combined with threshold tracking transcranial magnetic stimulation (TMS) to assess the anatomical and functional integrity of corticomotoneurons in asymptomatic SOD-1 mutation carriers. Methods: TMS studies were undertaken using a 90mm circular coil on 7 asymptomatic SOD-1 mutation carriers and results were compared to 62 healthy controls. DTI studies were carried out using a 3 Tesla magnetic resonance device in the same asymptomatic SOD-1 mutation carriers. Results were compared to age-matched healthy controls. Results: In contrast to previous findings, there were no significant differences in fractional anisotropy (SOD-1 mutation carriers 0.62±0.01; controls 0.61±0.02, P= 0.2) and trace apparent diffusion coefficient (SOD-1 mutation carriers 0.003±0.0001; controls 0.003±0.0001) in asymptomatic SOD-1 mutation carriers. Of further relevance, there were no significant differences in short interval intracortical inhibition (SOD-1 mutation carriers 7.9±3.4%; controls 8.5±1.1%, P= 0.26), intracortial facilitation (P= 0.5), MEP amplitude (P= 0.44), resting motor threshold (P= 0.36) and cortical silent period duration (P= 0.29). Conclusions: Combined anatomical and functional studies modalities established normal integrity of corticomotoneurons in asymptomatic SOD-1 mutation carrier subjects. Significance: Additional factors other than simply SOD-1 gene mutations expression are required to trigger cortical hyperexcitability and neurodegeneration in FALS. W.A. Cobb Young Investigator Award

Award-B Corticomotoneuronal function in asymptomatic SOD-1 mutation carriers

Objective: Diffusion tensor imaging (DTI) recently identified structural abnormalities of corticomotoneurons in asymptomatic copper/zinc superoxide-dismutase-1 (SOD-1) gene mutation carriers. The potential existence of longstanding corticomotoneuronal dysfunction would clearly have consequences for the medical management of asymptomatic SOD-1 mutation carriers. To clarify this unexpected finding, DTI techniques were combined with threshold tracking transcranial magnetic stimulation (TMS) to assess the anatomical and functional integrity of corticomotoneurons in asymptomatic SOD-1 mutation carriers. Methods: TMS studies were undertaken using a 90mm circular coil on 7 asymptomatic SOD-1 mutation carriers and results were compared to 62 healthy controls. DTI studies were carried out using a 3 Tesla magnetic resonance device in the same asymptomatic SOD-1 mutation carriers. Results were compared to age-matched healthy controls. Results: In contrast to previous findings, there were no significant differences in fractional anisotropy (SOD-1 mutation carriers 0.62±0.01; controls 0.61±0.02, P= 0.2) and trace apparent diffusion coefficient (SOD-1 mutation carriers 0.003±0.0001; controls 0.003±0.0001) in asymptomatic SOD-1 mutation carriers. Of further relevance, there were no significant differences in short interval intracortical inhibition (SOD-1 mutation carriers 7.9±3.4%; controls 8.5±1.1%, P= 0.26), intracortial facilitation (P= 0.5), MEP amplitude (P= 0.44), resting motor threshold (P= 0.36) and cortical silent period duration (P= 0.29). Conclusions: Combined anatomical and functional studies modalities established normal integrity of corticomotoneurons in asymptomatic SOD-1 mutation carrier subjects. Significance: Additional factors other than simply SOD-1 gene mutations expression are required to trigger cortical hyperexcitability and neurodegeneration in FALS. W.A. Cobb Young Investigator Award

Treatment for familial amyotrophic lateral sclerosis/motor neuron disease.

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a rare neurodegenerative disease. Approximately 5% to 7% of ALS/MND patients report a family history of a similarly affected relative. Superoxide dismutase-1 gene mutations are the cause in about 20% of familial cases. In those with non-familial (sporadic) ALS/MND the cause is unknown. Also unknown is whether patients with familial and sporadic ALS/MND respond differently to treatment. To systematically review the literature and to answer the specific question: 'Is there a difference in the response to treatment between patients with sporadic and familial forms of ALS?' In May 2006 we searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (January 1966 to May 2006) and EMBASE (January 1980 to May 2006) for randomized controlled trials (RCTs). Two review authors read the titles and abstracts of all articles and reviewed the full text of all possibly relevant articles. We scanned references of all included trials to identify additional relevant articles. For all trials eligible for inclusion we contacted the authors to request the necessary raw data. Studies had to meet two criteria: (a) randomized controlled study design, and (b) inclusion of patients with both familial and sporadic ALS/MND. We attempted to contact authors of all trials that met inclusion criteria. We obtained data regarding ALS/MND type (sporadic versus familial), treatment assignment (active versus placebo), survival and ALS Functional Rating Scale scores for four large RCTs that included 822 sporadic and 41 familial ALS patients. We could not obtain data from 25 potentially eligible studies (17 trial authors could not be contacted and eight were unwilling to provide data). There was no statistical evidence for a different response to treatment in patients with familial ALS/MND compared to those with sporadic ALS/MND. The pooled estimate of the hazard ratio for the interaction term (treatment x familial ALS) suggested a more beneficial response with respect to survival among patients with familial ALS/MND, but the result was not statistically significant. Estimates of the rate of decline on the ALS Functional Rating Scale also suggested a slightly better response to treatment among those with familial ALS/MND, but the result was not statistically significant. Future RCTs should document whether patients with familial ALS/MND are included and the presence or absence of a mutation in the superoxide dismutase-1 gene amongst those with familial ALS/MND.

Nuclear TAR DNA Binding Protein 43 Expression in Spinal Cord Neurons Correlates With the Clinical Course in Amyotrophic Lateral Sclerosis

TAR DNA binding protein 43 (TDP-43) has been considered a signature protein in frontotemporal dementia and amyotrophic lateral sclerosis (ALS), but not in ALS associated with the superoxide dismutase 1 (SOD1) gene mutations (ALS1). To clarify how TDP may be involved in ALS pathogenesis, clinical and pathological features in cases of sporadic ALS ([SALS] n = 18) and ALS1 (n = 6) were analyzed. In SALS patients with rapid clinical courses, TDP mislocalization (i.e. cytoplasmic staining and TDP-positive cytoplasmic inclusions) in anterior horn cells was frequent. In SALS patients with slow clinical courses, TDP-43 mislocalization was rare. In an ALS1 patient with the SOD1 gene mutation C111Y, there were numerous TDP-positive inclusions and colocalization of SOD1 and TDP. In mutant SOD1 transgenic (G93A) mice at the end stage (median, 256 days), TDP-positive inclusions and TDP colocalization with SOD1 were also observed; nuclear TDP-43 immunoreactivity was highly correlated with life span in these mice. In both humans and mice, nuclei that stained strongly for TDP were large and circular; weakly stained nuclei were atrophic or deformed. In conclusion, low levels of TDP expression in the nucleus cor relate with a rapid clinical course in SALS and in ALS1 model mice, suggesting that nuclear TDP may play a protective role against motor neuron death resulting from different underlying etiologies.

Comparative analysis of the time-dependent functional and molecular changes in spinal cord degeneration induced by the G93A SOD1 gene mutation and by mechanical compression

BackgroundMutations of the superoxide dismutase 1 (SOD1) gene are linked to amyotrophic lateral sclerosis (ALS), an invariably fatal neurological condition involving cortico-spinal degeneration. Mechanical injury can also determine spinal cord degeneration and act as a risk factor for the development of ALS.ResultsWe have performed a comparative ontological analysis of the gene expression profiles of thoracic cord samples from rats carrying the G93A SOD1 gene mutation and from wild-type littermates subjected to mechanical compression of the spinal cord. Common molecular responses and gene expression changes unique to each experimental paradigm were evaluated against the functional development of each animal model. Gene Ontology categories crucial to protein folding, extracellular matrix and axonal formation underwent early activation in both experimental paradigms, but decreased significantly in the spinal cord from animals recovering from injury after 7 days and from the G93A SOD1 mutant rats at end-stage disease. Functional improvement after compression coincided with a massive up-regulation of growth-promoting gene categories including factors involved in angiogenesis and transcription, overcoming the more transitory surge of pro-apoptotic components and cell-cycle genes. The cord from G93A SOD1 mutants showed persistent over-expression of apoptotic and stress molecules with fewer neurorestorative signals, while functional deterioration was ongoing.Conclusionthis study illustrates how cytoskeletal protein metabolism is central to trauma and genetically-induced spinal cord degeneration and elucidates the main molecular events accompanying functional recovery or decline in two different animal models of spinal cord degeneration.

A novel SOD1 gene mutation in a Korean family with amyotrophic lateral sclerosis

Background: Superoxide dismutase 1 (SOD1) gene mutations are responsible for approximately 20% of all familial amyotrophic lateral sclerosis (ALS) cases. However, these cases, especially those with SOD1 gene mutations, have not been reported in Korea. Objectives: The SOD1 gene in Korean family with ALS was screened for potential mutations and the clinical data was collected. Materials and methods: The clinical histories and neurological findings of the family members were obtained. Genomic DNA was isolated from the leukocytes of whole blood samples and the coding region of the SOD1 gene was analyzed by PCR and sequencing. Results: The family with ALS showed a novel missense mutation in the SOD1 gene, which was heterozygous for the mutation, GGC to GTT, causing the substitution of valine for glycine at codon 10 (Gly10Val) in exon 1. Clinically, the patients exhibited early onset and rapid disease progression. Conclusions: Familial ALS with a novel Gly10Val mutation in the SOD1 gene showed severe clinical features. The mutation lies in a region involved in a dimer contact in the three-dimensional structure of the SOD1 protein. This study expands the number of ALS-associated SOD1 gene mutations.

Copper chaperone for superoxide dismutase co-aggregates with superoxide dismutase 1 (SOD1) in neuronal Lewy body-like hyaline inclusions: an immunohistochemical study on familial amyotrophic lateral sclerosis with SOD1 gene mutation.

The copper chaperone for superoxide dismutase (CCS) interacts with Cu/Zn-binding superoxide dismutase 1 (SOD1) specifically and delivers copper to SOD1. To determine the role of the CCS-SOD1 interaction in the pathogenesis of SOD1-mutated familial amyotrophic lateral sclerosis (FALS) patients, we produced an affinity-purified rabbit antibody against CCS and investigated the immunohistochemical localization of both CCS and SOD1 in neuronal Lewy body-like hyaline inclusions (LBHIs) in the spinal cords of two FALS patients with a two-base pair deletion at codon 126 in the SOD1 gene and three FALS patients with an Ala to Val substitution at codon 4. The LBHIs in anterior horn cells from the five FALS patients showed identical immunoreactivities for CCS: the reaction product deposits with the antibody against CCS were generally restricted to the periphery of the core and halo-type LBHIs. The localizations of the immunoreactivities for CCS and SOD1 were similar in the inclusions: both CCS and SOD1 colocalized in neuronal LBHIs in the five mutant SOD1-linked FALS patients. Our results suggest that the specific interaction and aggregation of CCS-SOD1 (probably CCS-mutant SOD1) in SOD1-mutated FALS patients may amplify the formation of inclusions and emphasize a more marked mutant SOD1-mediated toxicity.