Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS population: should all sporadic ALS cases also be screened for SOD1?

BACKGROUND: SOD1 gene mutations are the most common identified cause of ALS, accounting for approximately 20% of familial ALS cases and around 4% of sporadic ALS cases. However, the prevalence of SOD1 varies in different ethnic groups. No previous epidemiological studies have been carried out in Catalonia. OBJECTIVE: To determine the prevalence of SOD1 gene mutations in a Catalan ALS population, and to analyze the genotype-phenotype relationship. MATERIALS AND METHODS: 30 different FALS pedigrees and 94 sporadic ALS patients were screened for SOD1 mutations using direct sequence analysis. RESULTS: Five of the 30 FALS pedigrees (16.6%) carried a SOD1 mutant. The mutations identified in this group were G37R, D76V, S105L, I112M and N139H. Four SOD1 mutants (4.25%) were found in the sporadic ALS group (SALS). The overall frequency (FALS plus SALS) of SOD1 mutations in our series was 6.45%. In the SALS group, D90A was identified in a patient presenting the typical Scandinavian phenotype. A 53-year-old woman with no family history of ALS carried the N139H mutation. Two unrelated sporadic ALS cases carried the A140A SOD1 mutant. CONCLUSIONS: The prevalence of the SOD1 mutation in FALS in Catalonia is similar to levels in other Mediterranean countries, but lower than those in reports studying the Belgian, Japanese, and Scottish populations. The prevalence of the SOD1 mutation was 4.25% in patients with no family history of ALS. These results may have significant repercussions on genetic counseling, and screening for the SOD1 mutation in sporadic ALS cases must therefore be considered.     

Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations. Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies. We recently identified TDP-43 as the major pathological protein in sporadic ALS. In this study, we investigated TDP-43 in a larger series of ALS cases (n = 111), including familial cases with and without SOD1 mutations. METHODS: Ubiquitin and TDP-43 immunohistochemistry was performed on postmortem tissue from sporadic ALS (n = 59), ALS with SOD1 mutations (n = 15), SOD-1-negative FALS (n = 11), and ALS with dementia (n = 26). Biochemical analysis was performed on representative cases from each group. RESULTS: All cases of sporadic ALS, ALS with dementia, and SOD1-negative FALS had neuronal and glial inclusions that were immunoreactive for both ubiquitin and TDP-43. Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43. Biochemical analysis of postmortem tissue from sporadic ALS and SOD1-negative FALS demonstrated pathological forms of TDP-43 that were absent in cases with SOD1 mutations. INTERPRETATION: These findings implicate pathological TDP-43 in the pathogenesis of sporadic ALS. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS.     

Superoxide dismutase gene mutations in Italian patients with familial and sporadic amyotrophic lateral sclerosis: identification of three novel missense mutations

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of the patients are sporadic cases (SALS), while 5-10% of the patients have a family history of ALS (familial ALS or FALS). Mutations in the gene coding for cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in about 20% of FALS cases. We found SOD1-gene mutations in five of 34 unrelated FALS, and in two of 44 SALS patients. Three FALS patients carried the previously described A4V (two cases) and L84F mutations (one case), while two FALS patients carried new missense mutations: a G12R substitution in exon 1, and a F45C substitution in exon 2, respectively. The newly identified mutations were both associated with a slowly progressive disease course. Two SALS patients carried the homozygous D90A and the heterozygous I113T mutation, respectively. In addition, in one SALS patient we identified an A95T amino acid substitution, that is apparently a non-pathogenic SOD1 variant. Our study increases the number of ALS-associated SOD1 gene mutations.     

SOD1 mutations in amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS), the most common form among motoneuron diseases, is characterized by a progressive neurodegenerative process involving motor neurons in the motor cortex, brain stem and spinal cord. Sporadic (SALS) accounts for the majority of patients but in about 10% of ALS cases the disease is inherited (FALS), usually as an autosomal dominant trait.In the present study we show the results of a referred based multicenter study on the distribution of SOD1 gene mutations in the largest cohort of Italian ALS patients described so far. Two hundred and sixty-four patients (39 FALS and 225 SALS) of Italian origin were studied. In 7 out of 39 FALS patients we found the following SOD1 gene mutations: i) a new G12R missense mutation in exon 1, found in a patient with a slowly progressive disease course; ii) the G41S mutation, in four unrelated patients with rapidly progressive course complicated with cognitive decline in two of them; iii) the L114F mutation, in a patient with a slowly progressive phenotype; iv) the D90A mutation, in a heterozygous patient with atypical phenotype. In addition, in one SALS patient a previously reported synonymous variant S59S was identified. In 17 (3 FALS and 14 SALS) out of 264 patients (6.4 %) the polymorphism A-->C at position 34 of intron 3 (IVS3: + 34 A-->C) was found, and in one FALS patient a novel variant IVS3 + 62 T-->C was identified.The frequency of SOD1 gene mutations (17.9 %) in FALS cases was comparable with that found in other surveys with a similar sample size of ALS cases. No SOD1 gene mutations have been identified in SALS cases. Within FALS cases, The most frequent mutation was the G41S identified in four FALS.     

TDP‐43 is consistently co‐localized with ubiquitinated inclusions in sporadic and Guam amyotrophic lateral sclerosis but not in familial amyotrophic lateral sclerosis with and without SOD1 mutations

The transactive response (TAR) DNA binding protein 43 (TDP‐43) has been recently implicated as a major component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS, motor neuron disease: MND) and ALS‐related disorders. In this study, we examined abnormal TDP‐43 pathology in 13 sporadic ALS (SALS), six familial ALS (FALS) with and without Cu/Zn superoxide dismutase (SOD1) mutations (SOD1‐FALS and non‐SOD1‐FALS), Guam ALS, two frontotemporal lobar degeneration with MND/ALS (FTLD‐MND/ALS), one FTLD with ubiquitin‐only‐immunoreactive inclusions (FTLD‐U) and two progressive supranuclear palsy (PSP). Sections from the spinal cord were processed for immunohistochemistry using antibodies against TDP‐43, ubiquitin, p62, cystatin C, phosphorylated tau protein (P‐tau; AT8), α‐synuclein and phosphorylated neurofilament protein (P‐NF). In 12 out of 13 SALS and both Guam ALS cases ubiquitin and p62‐immunoreactive (IR) neuronal inclusions co‐localized with TDP‐43. In three out of four SOD1‐FALS and one of two non‐SOD1‐FALS cases, TDP‐43‐IR inclusions were absent despite the presence of p62 and/or ubiquitin‐IR inclusions. However, a single TDP‐43‐IR neuronal inclusion co‐localized with p62 and ubiquitin in one SOD1‐FALS (His48Gln) case. Except for one neuron in a Guam case, all TDP‐43‐IR neuronal inclusions were negative for P‐tau (AT8). TDP‐43‐IR glial inclusions and neurites were also demonstrated. The TDP‐43 is a consistent component of the ubiquitinated inclusions in SALS and Guam ALS, but TDP‐43‐IR inclusions are absent or scarce in SOD1‐FALS.     

SOD1 and cognitive dysfunction in familial amyotrophic lateral sclerosis

Background   Sporadic Amyotrophic Lateral Sclerosis (sALS) is associated with frontotemporal dementia (ALS-FTD) or milder deficits of cognitive (predominantly executive) dysfunction (ALSCi) in some patients. Some forms of familial ALS (FALS) have a family history of FTD, ALS-FTD, or both, but there have been few reports of ALS-FTD in FALS patients with mutations of the gene superoxide dismutase-1 (SOD1 FALS). The aim of this study was to test the hypothesis that ALSCi may be found in non-SOD1 FALS, but that SOD1 FALS patients would show little or no evidence of cognitive change. Methods   A neuropsychological test battery was administered to 41 SALS patients, 35 control participants, 7 FALS patients with a SOD1 mutation (SOD1 FALS) and 10 FALS patients without a SOD1 mutation (non-SOD1 FALS). Results   Relative to control participants, non-SOD1 FALS patients had impaired performance on written verbal fluency and confrontation naming, and reported higher levels of executive behavioural problems. These deficits were absent in SOD1 FALS patients. SALS patients performed poorer than controls only on the Graded Naming Test. All ALS groups had higher levels of behavioural apathy and emotional lability than were found in control participants. Cognitive domains of memory, receptive language, and visuospatial perception were spared. Groups were matched for age, gender, premorbid full-scale IQ, anxiety and depression. Discussion   Individuals with SOD1 gene mutations are less likely to have significant cognitive changes compared to non-SOD1 FALS patients. Cognitive abnormalities in ALS are heterogeneous and may reflect underlying genetic variations rather than a simple spectrum of extra-motor involvement.     

S100A6 overexpression within astrocytes associated with impaired axons from both ALS mouse model and human patients

Astrogliosis is one of the earliest pathological changes observed in neurodegenerative diseases in general and in amyotrophic lateral sclerosis (ALS) in particular. ALS is characterized by selective degeneration of motoneurons. There are 2 forms of the disease: sporadic ALS (SALS), comprising 90%-95% of cases, and familial ALS (FALS), comprising 5%-10% of cases. FALS is an age-dependent autosomal dominant disorder in which mutations in the homodimeric enzyme Cu/ Zn superoxide dismutase 1 (SOD1) is linked to the disease. The animal model for this disease is a transgenic mouse expressing the mutated human SOD1(G93A) gene. Here we show by immunohistochemistry and double immunofluorescence that astrocytes located near impaired axons of motoneurons that were selectively programmed to die overexpressed S100A6, a Ca2+/Zn2+ binding protein able to translocate into the nucleus. Transgenic mice overexpressing the mutated human SOD1 gene and patients suffering from SALS showed this selective astrocytic S100A6 expression. For instance, the pyramidal tract could be macroscopically detected on S100A6-labeled spinal cord and brainstem sections from SALS patients. Transgenic mice overexpressing the non-mutated SOD1 gene did not overexpress S100A6, although glial fibrillary associated protein astrogliosis was seen. Although these results do not give any clue about the beneficial or detrimental role played by S100A6, its induction may be assumed to appropriately serve some function(s).     

Cu/Zn superoxide dismutase activity at different ages in sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive disorder resulting from degeneration of motor neurons in the brain and spinal cord. Sporadic ALS (SALS) accounts for the majority of patients and the familial form (FALS) represents fewer than 10% of all cases. Since it was found that there are Cu/Zn superoxide dismutase (SODI) gene mutations in 20% of FALS patients and that FALS and SALS patients show similar clinical features, it has been postulated that both may share a common physiopathological mechanism. We studied Cu/Zn SOD1 activity in cytosolic extracts of erythrocytes from 125 normal individuals and 40 SALS patients. We found that enzyme activity does not change with age in control subjects and tends to decrease in most SALS patients older than 60 years. A subpopulation of five SALS patients had significantly increased SOD1 activity; four of these patients over 70 years old. There was no correlation between enzyme activity and time of onset of the disease, or clinical forms of the illness. The variation in SOD1 activity in ageing SALS patients compared with younger patients suggests that they may undergo an oxidative disbalance contributing to the development of the disease.     

L-carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis

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.     

Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis.

Dominant mutations in the copper/zinc superoxide dismutase (SOD1) gene have been observed in 15-20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism by which SOD1 mutations result in motor neuron degeneration in FALS mice partly involves oxidative damage and an increased peroxidase activity of the mutant SOD1. A new therapeutic approach designed to eliminate the substrate of this peroxidase activity was examined in two lines of transgenic mice expressing the FALS-linked mutation glycine to alanine (G93A). We investigated the ability of putrescine-modified catalase (PUT-CAT), an antioxidant enzyme that removes hydrogen peroxide and has increased permeability at the blood-brain barrier, to modify the time course of the SOD1 mutation-induced motor neuron disease in these FALS mice. Continuous, subcutaneous administration of PUT-CAT significantly delayed the age at which onset of clinical disease occurred (indicated by loss of splay and/or tremors of hindlimbs) in a high-expressor line of FALS transgenic mice. Intraperitoneal injection of PUT-CAT given two times per week also significantly delayed the onset of clinical disease in a low-expressor line of FALS mice. PUT-CAT also significantly delayed the age at which clinical weakness developed (quantified by measuring the shortening of stride length) in both lines of FALS animals. No significant changes were observed in the survival times of the high-expressor FALS mice in any of the treatment groups. However, a trend toward a prolongation of survival was observed in the PUT-CAT-treated low-expressor FALS mice. These results support the role of free radical-mediated damage in the cascade of events leading to motor neurodegeneration in FALS and indicate that PUT-CAT interacts with a critical step in this cascade to delay the onset of clinical disease as well as the development of clinical weakness in FALS transgenic mice.     

Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy.

OBJECTIVE: To characterize the motor neuron dysfunction in two models by performing physiologic and morphometric studies. BACKGROUND: Mutations in the gene encoding cytosolic superoxide dismutase 1 (SOD1) account for 25% of familial ALS (FALS). Transgenes with these mutations produce a pattern of lower motor neuron degeneration similar to that seen in patients with FALS. In contrast, mice lacking SOD1 develop subtle motor symptoms by approximately 6 months of age. METHODS: Physiologic measurements, including motor conduction and motor unit estimation, were analyzed in normal mice, mice bearing the human transgene for FALS (mFALS mice), and knockout mice deficient in SOD1 (SOD1-KO). In addition, morphometric analysis was performed on the spinal cords of SOD1-KO and normal mice. RESULTS: In mFALS mice, the motor unit number in the distal hind limb declined before behavioral abnormalities appeared, and motor unit size increased. Compound motor action potential amplitude and distal motor latency remained normal until later in the disease. In SOD1-KO mice, motor unit numbers were reduced early but declined slowly with age. In contrast with the mFALS mice, SOD1-KO mice demonstrated only a modest increase in motor unit size. Morphometric analysis of the spinal cords from normal and SOD1-KO mice showed no significant differences in the number and size of motor neurons. CONCLUSIONS: The physiologic abnormalities in mFALS mice resemble those in human ALS. SOD1-deficient mice exhibit a qualitatively different pattern of motor unit remodeling that suggests that axonal sprouting and reinnervation of denervated muscle fibers are functionally impaired in the absence of SOD1.     

Molecular mechanism of ALS and a possible gene therapy]

We report clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with four different missense point mutations in exons 1, 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene, that result in amino acid substitutions of cysteine 6 by phenylalanin (C 6 F), histidine 46 by arginine (H46R), leucine 84 by valine (L84V), isoleucine 104 by phenylalanine (I104F), and valine 148 by isoleucine (V148I), in five Japanese families. Although features of progressive neurogenic muscular atrophy was common in patients of these families, patients of each family showed characteristic clinical features. Immunoreactivity for Cu/Zn SOD of the motor neurons was not different between the ALS and controls. In contrast, immunoreactivity for NT was densely detected in motor neurons of ALS while that was not or was only minimally detected in those of controls. Adenovirus-mediated E. coli LacZ gene was transferred and expressed both in the muscle and spinal cord of transgenic mice. These results suggest that familial ALS with different mutations of the Cu/Zn SOD gene showed each clinical characteristics, that nitration of protein-tyrosine residue is upregulated in motor neurons of the spinal cord of ALS, and that there could be a possible future therapy of ALS with exogenous gene transfer.     

TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation

Recently, 43-kDa TAR DNA-binding protein (TDP-43) was identified as a component of ubiquitinated inclusions (UIs) in sporadic amyotrophic lateral sclerosis (SALS). To clarify whether TDP-43 immunoreactivity is present in neuronal inclusions in familial ALS (FALS), we examined immunohistochemically the brains and spinal cords from four cases of FALS, two with Cu/Zn superoxide dismutase (SOD1) gene mutation and two without, together with three cases of SALS and three control subjects, using two antibodies, one polyclonal and one monoclonal, against TDP-43. Neuropathologically, the SOD1-related FALS cases were characterized by Lewy body-like hyaline inclusions (LBHIs) in the lower motor neurons. On the other hand, the SOD1-unrelated FALS cases showed degeneration restricted to the upper and lower motor neuron systems, with Bunina bodies (BBs) and UIs in the lower motor neurons, being indistinguishable from SALS. No cytoplasmic TDP-43 immunoreactivity was observed in the control subjects or SOD1-related FALS cases; LBHIs were ubiquitinated, but negative for TDP-43. UIs observed in the SALS and SOD1-unrelated FALS cases were clearly positive for TDP-43. BBs were negative for this protein. Interestingly, in these SALS and FALS cases, glial cells were also found to have cytoplasmic TDP-43-positive inclusions. These findings indicate that the histological and molecular pathology of SALS can occur as a phenotype of FALS without SOD1 mutation.     

Molecular basis of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration with unclear etiology and no effective treatment to date. ALS is, however, increasingly recognized as a multisystem disorder associated with impaired cognition. The overlap between ALS and dementia at clinical, genetic and neuropathologic levels indicates a spectrum of clinical phenotypes that may include features of frontotemporal lobar degeneration (FTLD). Most cases of ALS are sporadic (SALS), but approximately 10% of all ALS cases are familial ALS (FALS). Mutations in the Cu/Zn superoxide dismutase-1 gene (SOD-1) occur in about 20% of FALS cases. Mutations in the TAR DNA-binding protein 43 gene (TARDBP or TDP-43) may occur in 3-4% of FALS cases, and less frequently, in FTLD. Recently, mutations in the fused in sarcoma/translation in liposarcoma gene (FUS/TLS) were identified as causing about 4-5% of FALS, SALS, and FTLD cases, but not SOD-1 ALS cases, indicating a pathogenic role of FUS, together with TDP-43, in possibly all types of ALS, except for SOD-1 linked ALS. TDP-43 and FUS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. Thus, TARDBP and FUS/TLS mutations define a novel class of neurodegenerative diseases called TDP-43- and FUS-proteinopathies, in which both misfolded proteins are novel targets for the development of therapeutics in this spectrum of diseases. However, SOD-1 linked ALS may have a pathogenic pathway distinct from other types of ALS.     

Superoxyde dismutase 1 gene abnormalities in familial amyotrophic lateral sclerosis: phenotype/genotype correlations. The French experience and review of the literature

About 20 p. cent of cases of amyotrophic lateral sclerosis are familial (FALS). Fifteen percent of FALS cases are associated with an abnormality in the superoxide dismutase 1 (SOD1) gene. To date, more than 100 different genetic abnormalities have been reported, all except two are autosomal dominant. The clinical characteristics of patients presenting with FALS associated with an SOD1 abnormality is homogeneous when there is no doubt about the hereditary aspect of the genetic abnormality: mean age at onset 42 years, limb onset, slow evolution. Except when present in the setting of a clearly inherited disease (FALS) (several patients through several generations), the causality of a given SOD1 mutation often remains an open question. Consequently, search for SOD1 mutation is not warranted when atypical features such as young age at onset or slow progression are present. Conversely, a complete family study is justified to determine the precise role of a given SOD1 mutation because of the large number of potential SOD1 mutations, the variability of the transmission mode, and the non-exceptional absence of proven causality for ALS. Specific cases where a frequent SOD1 mutation with a recognized causal effect is recognized (no more than 15 out of more than 90 mutations) would be an exception.     

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction.     

Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models

Peroxiredoxin-ll (Prxll) and glutathione peroxidase-l (GPxl) are regulators of the redox system that is one of the most crucial supporting systems in neurons. This system is an antioxidant enzyme defense system and is synchronously linked to other important cell supporting systems. To clarify the common self-survival mechanism of the residual motor neurons affected by amyotrophic lateral sclerosis (ALS), we examined motor neurons from 40 patients with sporadic ALS (SALS) and 5 patients with superoxide dismutase 1 (SOD1)-mutated familial ALS (FALS) from two different families (frame-shift 126 mutation and A4 V) as well as four different strains of the SOD1-mutated ALS models (H46R/G93A rats and G1H/G1L-G93A mice). We investigated the immunohistochemical expression of Prxll/GPxl in motor neurons from the viewpoint of the redox system. In normal subjects, Prxll/GPxl immunoreactivity in the anterior horns of the normal spinal cords of humans, rats and mice was primarily identified in the neurons: cytoplasmic staining was observed in almost all of the motor neurons. Histologically, the number of spinal motor neurons in ALS decreased with disease progression. Immunohistochemically, the number of neurons negative for Prxll/GPxl increased with ALS disease progression. Some residual motor neurons coexpressing Prxll/GPxl were, however, observed throughout the clinical courses in some cases of SALS patients, SOD1-mutated FALS patients, and ALS animal models. In particular, motor neurons overexpressing Prxll/GPxl, i.e., neurons showing redox system up-regulation, were commonly evident during the clinical courses in ALS. For patients with SALS, motor neurons overexpressing Prxll/GPxl were present mainly within approximately 3 years after disease onset, and these overexpressing neurons thereafter decreased in number dramatically as the disease progressed. For SOD1-mutated FALS patients, like in SALS patients, certain residual motor neurons without inclusions also overexpressed Prxll/GPxl in the short-term-surviving FALS patients. In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of Prxll/GPxl during their clinical courses. At the terminal stage of ALS, however, a disruption of this common Prxll/GPxl-overexpression mechanism in neurons was observed. These findings lead us to the conclusion that the residual ALS neurons showing redox system up-regulation would be less susceptible to ALS stress and protect themselves from ALS neuronal death, whereas the breakdown of this redox system at the advanced disease stage accelerates neuronal degeneration and/or the process of neuronal death.     

Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons (MNs). Approximately 10% of ALS cases are familial (known as FALS), and  20% of FALS cases are caused by mutations in Cu/Zn superoxide dismutase type 1 (SOD1). Mutant (MT) SOD1 induces FALS as a result of a toxicity that remains poorly defined. Several studies suggest that the toxicity involves a non-cell autonomous mechanism. In this study, we generated transgenic mice that had a restricted and repressible expression of MTSOD1 in spinal MNs and interneurons. Although the transgenic mice were not weak, they weighed less than control mice and had pathological and immunohistochemical abnormalities of MNs confined to cells that expressed MTSOD1. These results suggest that MTSOD1-induced MN degeneration is at least partly cell autonomous. Mouse models similar to the one presented here will be valuable for spatially and temporally controlling expression of mutant genes involved in neurodegenerative diseases.     

A clinicopathological study of a patient with familial amyotrophic lateral sclerosis associated with a two base pair deletion in the copper/zinc superoxide dismutase (SOD1) gene

The recognition of mutations in the copper/ zinc superoxide dismutase (SOD1) gene in familial amyotrophic lateral sclerosis (FALS) has been a landmark in ALS research. We report a clinicopathological study of a female patient with FALS showing a two base pair deletion in exon 5 of the SOD1 gene. Her clinical course was rapid and she died 2 years after the onset. The SOD1 activity was down to 30% of the normal level. Western blot analysis did not reveal the mutant protein which was expected to be ∼2.4 kDa smaller than normal SOD1 protein in molecular mass. In contrast to the neuropathological findings of the previously reported cases showing the same mutation, our case was characterized by sparing of the dorsal column and the presence of only a modest number of intracytoplasmic eosinophilic inclusions showing weak or partial immunoreaction for neurofilament and negative reaction for SOD1. Thus, the same mutation in the SOD1 gene does not necessarily induce consistent pathological changes in the central nervous system. Received: 7 March 1997 / Revised, accepted: 9 June 1997