Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: A decade of discoveries, defects and disputes
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.
- "Also frame-shift deletions and insertions, all clustered in exons 4 and 5, which lead to a premature truncation of the protein have been described (Figure 2). Collectively, SOD1 mutations are found in ~20% of all FALS patients, and in ~3% of SALS cases . In Italian ALS population, different screening have been performed [2, 18] and both confirmed that the percentage of mutation in SOD1 gene in Italian SALS was 4.5%. "
[Show abstract] [Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a disease of variable severity in terms of speed of progression of the disease course. We found a similar variability in disease onset and progression of 2 familial ALS mouse strains, despite the fact that they carry the same transgene copy number and express the same amount of mutant SOD1G93A messenger RNA and protein in the central nervous system. Comparative analysis of 2 SOD1G93A mouse strains highlights differences associated with the disease severity that are unrelated to the degree of motor neuron loss but that appear to promote early dysfunction of these cells linked to protein aggregation. Features of fast progressing phenotype are (1) abundant protein aggregates containing mutant SOD1 and multiple chaperones; (2) low basal expression of the chaperone alpha-B-crystallin (CRYAB) and β5 subunits of proteasome; and (3) downregulation of proteasome subunit expression at disease onset. In contrast, high levels of functional chaperones such as cyclophillin-A and CRYAB, combined with delayed alteration of expression of proteasome subunits and the sequestration of TDP43 into aggregates, are features associated with a more slowly progressing pathology. These data support the hypothesis that impairment of protein homeostasis caused by low-soluble chaperone levels, together with malfunction of the proteasome degradation machinery, contributes to accelerate motor neuron dysfunction and progression of disease symptoms. Therefore, modulating the activity of these systems could represent a rational therapeutic strategy for slowing down disease progression in SOD1-related ALS.0Comments 4Citations
- "These features suggest the presence of gene modifiers and pathways that specifically affect the disease phenotype (Camu et al., 1999). For example, mutations in the Cu-Zn superoxide dismutase 1 (SOD1) gene (>140 discovered, http://alsod.iop.kcl.ac.uk), which are responsible for 1/5th of fALS cases (Andersen et al., 2003), are characterized by a considerable interfamilial and intrafamilial variabilities in the phenotype (Cudkowicz et al., 1997). These SOD1 gene mutations, the majority of which are missense substitutions, result in a toxic gain of function of the enzyme (Valentine et al., 2005). "
[Show abstract] [Hide abstract] 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.0Comments 9Citations
- "The majority of ALS cases are sporadic but around 10% are familial in origin . Cu/Zn Superoxide Dismutase 1 (SOD1) was the first gene identified as mutated in ALS , and accounts for approximately 2% of all ALS cases , . SOD1 is a ubiquitously expressed metalloenzyme that catalyses the dismutation of superoxide radicals into hydrogen peroxide and molecular oxygen. "