Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes.
ABSTRACT Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) ten years ago, testing for SOD1 gene mutations has become a part of the investigation of patients with suspected motor neuron disease. We searched for novel SOD1 mutations and for clinical characteristics of patients with these mutations.
Analysis was made of patient files at the Neurogenetic DNA Diagnostic Laboratory at Massachusetts General Hospital. We also scrutinized available medical records and examined patients with the different SOD1 mutations.
One hundred and forty eight (148) of 2045 amyotrophic lateral sclerosis (ALS) patients carried a disease-associated mutation in the SOD1 gene. The most prevalent was the A4V missense mutation, found in 41% of those patients. Sixteen novel exonic mutations (L8V, F20C, Q22L, H48R, T54R, S591, V87A, T88deltaTAD, A89T, V97M, S105deltaSL, V118L, D124G, G141X, G147R, 11515) were found, bringing the total number of SOD1 gene mutations in ALS to 105.
Mutations in the SOD1 gene are found both in sporadic and familial ALS cases without any definite predilection for any part of the gene. A common structural denominator for the 16 novel mutations or previously reported mutations is not obvious. Similarly, the nature of the putative acquired toxic function of mutant SOD1 remains unresolved. We conclude that patients with SOD1 mutations may infrequently show symptoms and signs unrelated to the motor systems, sometimes obscuring the diagnosis of ALS.
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ABSTRACT: BACKGROUND Therapies designed to decrease the level of SOD1 are currently in a clinical trial for patients with superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis (ALS). OBJECTIVE To determine whether the SOD1 protein in cerebral spinal fluid (CSF) may be a pharmacodynamic marker for antisense oligonucleotide therapy and a disease marker for ALS. DESIGN Antisense oligonucleotides targeting human SOD1 were administered to rats expressing SOD1G93A. The human SOD1 protein levels were measured in the rats' brain and CSF samples. In human CSF samples, the following proteins were measured: SOD1, tau, phosphorylated tau, VILIP-1, and YKL-40. PARTICIPANTS Ninety-three participants with ALS, 88 healthy controls, and 89 controls with a neurological disease (55 with dementia of the Alzheimer type, 19 with multiple sclerosis, and 15 with peripheral neuropathy). RESULTS Antisense oligonucleotide-treated SOD1G93A rats had decreased human SOD1 messenger RNA levels (mean [SD] decrease of 69% [4%]) and decreased protein levels (mean [SD] decrease of 48% [14%]) in the brain. The rats' CSF samples showed a similar decrease in hSOD1 levels (mean [SD] decrease of 42% [14%]). In human CSF samples, the SOD1 levels varied a mean (SD) 7.1% (5.7%) after additional measurements, separated by months, were performed. The CSF SOD1 levels were higher in the participants with ALS (mean [SE] level, 172  ng/mL; P < .05) and the controls with a neurological disease (mean [SE] level, 172  ng/mL; P < .05) than in the healthy controls (mean [SE] level, 134  ng/mL). Elevated CSF SOD1 levels did not correlate with disease characteristics in participants with ALS or controls with dementia of the Alzheimer type, but they did correlate with tau, phosphorylated tau, VILIP-1 and YKL-40 levels in controls with dementia of the Alzheimer type. CONCLUSIONS SOD1 in CSF may be an excellent pharmacodynamic marker for SOD1-lowering therapies because antisense oligonucleotide therapy lowers protein levels in the rat brain and rat CSF samples and because SOD1 levels in CSF samples from humans are stable over time.Archives of neurology 11/2012; · 7.58 Impact Factor
Article: Ventilatory Control in ALS.[Show abstract] [Hide abstract]
ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease. ALS selectively causes degeneration in upper and lower (spinal) motor neurons, leading to muscle weakness, paralysis and death by ventilatory failure. Although ventilatory failure is generally the cause of death in ALS, little is known concerning the impact of this disorder on respiratory motor neurons, the consequences of respiratory motor neuron cell death, or the ability of the respiratory control system to "fight back"via mechanisms of compensatory respiratory plasticity. Here we review known effects of ALS on breathing, including possible effects on rhythm generation, respiratory motor neurons, and their target organs: the respiratory muscles. We consider evidence for spontaneous compensatory plasticity, preserving breathing well into disease progression despite dramatic loss of spinal respiratory motor neurons. Finally, we review current and potential therapeutic approaches directed toward preserving the capacity to breathe in ALS patients.Respiratory Physiology & Neurobiology 05/2013; · 2.05 Impact Factor
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ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. Substantial evidence implicates oxidative stress and mitochondrial dysfunction as early events in disease progression. Our aim was to ascertain whether mutation of the SOD1 protein increases metabolic functional susceptibility to oxidative stress. Here we used a motor neuron-like cell line (NSC34) stably transfected with various human mutant SOD1 transgenes (G93A, G37R, H48Q) to investigate the impact of oxidative stress on cell viability and metabolic function within intact cells. NSC34 cells expressing mutant SOD1 showed a dose dependent reduction in cell viability when exposed to oxidative stress induced by hydrogen peroxide, with variation between mutations. The G93A transfectants showed greater cell death and LDH release compared to cells transfected with the other SOD1 mutations, and H48Q showed an accelerated decline at later time points. Differences in mitochondrial bioenergetics, including mitochondrial respiration, coupling efficiency and proton leak, were identified between the mutations, consistent with the differences observed in viability. NSC34 cells expressing G93A SOD1 displayed reduced coupled respiration and mitochondrial membrane potential compared to controls. Furthermore, the G93A mutation had significantly increased metabolic susceptibility to oxidative stress, with hydrogen peroxide increasing ROS production, reducing both cellular oxygen consumption and glycolytic flux in the cell. This study highlights bioenergetic defects within a cellular model of ALS and suggests that oxidative stress is not only detrimental to oxygen consumption but also glycolytic flux, which could lead to an energy deficit in the cell.PLoS ONE 01/2013; 8(6):e68256. · 3.73 Impact Factor