Showing papers on "Amyotrophic lateral sclerosis published in 2001"

From charcot to lou gehrig: deciphering selective motor neuron death in als

Abstract: Since its description by Charcot more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in amyotrophic lateral sclerosis has remained a mystery. Modern genetics has now identified mutations in two genes — SOD1 and ALS2 — as primary causes of the disease, and has implicated others as potential contributors. Insights into these abnormalities, together with errors in the handling of synaptic glutamate and the potential excitotoxic response that this alteration provokes, have provided leads for the development of new strategies to identify an as yet elusive remedy for this progressive, fatal disorder.

The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.

Abstract: Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).

A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.

Abstract: Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.

Neuron-Specific Expression of Mutant Superoxide Dismutase 1 in Transgenic Mice Does Not Lead to Motor Impairment

Abstract: Mutations were identified in the Cu/Zn superoxide dismutase gene (SOD1) in approximately 15% of patients with familial amyotrophic lateral sclerosis. Transgenic animals expressing mutant SOD1 in all tissues develop an ALS-like phenotype. To determine whether neuron-specific expression of mutant SOD1 is sufficient to produce such a phenotype, we generated transgenic animals carrying the G37R mutation that is associated with the familial form of ALS (FALS), which is driven by the neurofilament light chain promoter. The transgenic animals express high levels of the human SOD1 protein in neuronal tissues, especially in the large motor neurons of the spinal cord, but they show no apparent motor deficit at up to 1.5 years of age. Our animal model suggests that neuron-specific expression of ALS-associated mutant human SOD1 may not be sufficient for the development of the disease in mice.

Immune reactivity in a mouse model of familial ALS correlates with disease progression

Abstract: Objective : The cause of motor neuron death in ALS is incompletely understood. This study aims to define the potential involvement of nonneuronal immune-inflammatory factors in the destruction of motor neurons in mutant superoxide dismutase-1 ( SOD1 ) transgenic mice as a model of ALS. Background : The presence of activated microglia, IgG and its receptor for Fc portion (FcγRI), and T lymphocytes in the spinal cord of both patients with ALS and experimental animal models of motor neuron disease strongly suggests that immune-inflammatory factors may be actively involved in the disease process. Methods : The expression of immune-inflammatory factors was followed in both human mutant (G93A) SOD1 transgenic mice and human wild-type SOD1 transgenic mice, at different ages (40, 80, and 120 days). Fixed, frozen, free-floating sections of the lumbar spinal cord were stained with antibodies against CD11b, IgG, FcγRI, intercellular adhesion molecule-1 (ICAM-1), CD3, and glial fibrillary acidic protein. Results : The earliest change observed was the upregulation of ICAM-1 in the ventral lumbar spinal cord of 40-day-old mutant SOD1 mice. IgG and FcγRI reactivities were detected on motor neurons as early as 40 days and on microglial cells at later stages. Microglial activation was first evident in the ventral horn at 80 days, whereas reactive astrocytes and T cells became most prominent in 120-day-old mutant SOD1 mice. Conclusion : The upregulation of proinflammatory factors during early presymptomatic stages as well as the expansion of immune activation as disease progresses in mutant SOD1 transgenic mice suggest that immune-inflammatory mechanisms could contribute to disease progression.

Rats Expressing Human Cytosolic Copper–Zinc Superoxide Dismutase Transgenes with Amyotrophic Lateral Sclerosis: Associated Mutations Develop Motor Neuron Disease

Abstract: Some cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding cytosolic, copper-zinc superoxide dismutase (SOD1). We report here that rats that express a human SOD1 transgene with two different ALS-associated mutations (G93A and H46R) develop striking motor neuron degeneration and paralysis. As in the human disease and transgenic ALS mice, pathological analysis demonstrates selective loss of motor neurons in the spinal cords of these transgenic rats. In spinal cord tissues, this is accompanied by activation of apoptotic genes known to be activated by mutant SOD1 protein in vitro and in vivo. These animals provide additional support for the proposition that motor neuron death in SOD1-related ALS reflects one or more acquired, neurotoxic properties of the mutant SOD1 protein. The larger size of this rat model as compared with the ALS mice will facilitate studies involving manipulations of spinal fluid (implantation of intrathecal catheters for chronic therapeutic studies; CSF sampling) and spinal cord (e.g., direct administration of viral- and cell-mediated therapies).

Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis.

Abstract: Mutations in the copper/zinc superoxide dismutase (mSOD1) gene are associated with a familial form of amyotrophic lateral sclerosis (ALS), and their expression in transgenic mice produces an ALS-like syndrome Recent observations suggest a role for inflammatory-related events in the progression and propagation of the neurodegenerative process in ALS Consistent with this view, the present study demonstrates that, during the course of the disease, the expression of cyclooxygenase type 2 (Cox-2), a key enzyme in the synthesis of prostanoids, which are potent mediators of inflammation, is dramatically increased In both early symptomatic and end-stage transgenic mSOD1 mice, neurons and, to a lesser extent, glial cells in the anterior horn of the spinal cord exhibit robust Cox-2 immunoreactivity Cox-2 mRNA and protein levels and catalytic activity are also significantly increased in the spinal cord of the transgenic mSOD1 mice The time course of the spinal cord Cox-2 upregulation parallels that of motor neuronal loss in transgenic mSOD1 mice We also show that Cox-2 activity is dramatically increased in postmortem spinal cord samples from sporadic ALS patients We speculate that Cox-2 upregulation, through its pivotal role in inflammation, is instrumental in the ALS neurodegenerative process and that Cox-2 inhibition may be a valuable therapeutic avenue for the treatment of ALS

Recruitment of the Mitochondrial-Dependent Apoptotic Pathway in Amyotrophic Lateral Sclerosis

Abstract: Molecular mechanisms of apoptosis may participate in motor neuron degeneration produced by mutant superoxide dismutase-1 (mSOD1), the only proven cause of amyotrophic lateral sclerosis (ALS). Consistent with this, here we show that the proapoptotic protein Bax translocates from the cytosol to the mitochondria, whereas cytochrome c translocates from the mitochondria to the cytosol in spinal cords of transgenic mSOD1 mice during the progression of the disease. Concomitantly, caspase-9 is activated in the spinal cord of transgenic mSOD1 mice. Only in end-stage transgenic mSOD1 mice is the downstream caspase-7 activated and the inhibitor of apoptosis, XIAP, cleaved. These results indicate a sequential recruitment of molecular elements of the mitochondrial-dependent apoptotic pathway in transgenic mSOD1 mice. We also provide immunohistochemical evidence that cytochrome c translocation occurs in the spinal cord of sporadic ALS patients. Collectively, these data suggest that the mitochondrial-dependent apoptotic pathway may contribute to the demise of motor neurons in ALS and that targeting key molecules of this cascade may prove to be neuroprotective.

A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group.

Abstract: INTRODUCTION: Increasing evidence suggests that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E ( f -tocopherol) has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS. The current study was designed to determine whether a-tocopherol (500 mg b.i.d.) may be efficacious in the treatment of ALS. METHODS: Two hundred and eighty-nine patients with ALS of less than 5 years duration, treated with riluzole, were enrolled in this study, and were randomly assigned to receive either a-tocopherol or placebo daily for one year. The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale. Patients were assessed at entry, and every 3 months thereafter during the study period. Survival was also recorded. Biochemical markers of oxidative stress were measured in a subset of patients ...

Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays.

Abstract: In order to obtain insight into the aetiology and pathogenesis of amyotrophic lateral sclerosis (ALS), high-density gene discovery arrays (GDA human version 1.2) containing 18 400 non-redundant EST cDNAs pooled from different tissue libraries have been used to monitor gene expression in lumbar spinal cord from ALS cases compared with controls. Quantitative filter analysis revealed differential expression of cDNAs normalized to internal standards. These candidates have been further investigated and their expression in spinal cord characterized in a panel of ALS and control subjects. Significant differential expression was obtained for 14 genes, 13 being elevated (up to six-fold) and one decreased (by 80%) in ALS. Amongst those elevated in ALS were thioredoxin and glial fibrilary acid protein, which have already been shown to be up-regulated in ALS, thus supporting the reliability of this approach. The other differentially regulated transcripts confirmed in the expression studies represent potential candidates in ALS pathogenesis being involved in antioxidant systems, neuroinflammation, the regulation of motor neurone function, lipid metabolism, protease inhibition and protection against apoptosis. The use of the GDA system has greatly facilitated the screening and retrieval of sequence information and has generated useful information on the cascade of molecular events occurring in ALS and potentially may highlight new candidates playing a role in the aetiology and progression of this disease.

Mechanisms of neurodegeneration in amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is the most common variant of motor neurone disease affecting adults that usually strikes during mid to late life. Its aetiology is still poorly understood, although a major breakthrough came with the discovery that mutations in the Cu/Zn superoxide dismutase (SOD1) gene affect approximately 20% of patients with familial ALS. Experiments using both transgenic mice and ALS tissues have been useful in delineating other genetic defects in ALS. However, because only a subset of cases can be attributed to one particular molecular defect (such as mutation of SOD1 or the gene encoding neurofilament H), the aetiology of ALS is likely to be multifactorial. This review discusses the major mechanisms of neurodegeneration in ALS, such as oxidative stress, glutaminergic excitotoxicity, damage to vital organelles, and aberrant protein aggregation.

Volumetric analysis reveals corticospinal tract degeneration and extramotor involvement in ALS.

Abstract: Background: Pathologic changes in the motor cortex and corticospinal tracts in ALS may be reflected by abnormal signal intensities on conventional MRI. The sensitivity of these changes in detecting underlying pathology remains unclear. Method: The authors used automated image analysis to quantify volumes of cerebral gray and white matter in 16 patients with ALS (eight limb onset, eight bulbar onset) and eight normal controls. Previously they had demonstrated a reduction in N-acetyl aspartate/creatine + phosphocreatine (NAA/[Cr + PCr]) measured by 1 H-MRS in the subcortical white matter in the motor cortex region in the patients with bulbar-onset ALS. To determine whether this resulted from axonal degeneration, they also compared gray and white matter volumes in the patients with limb- and bulbar-onset ALS. Results: There were no differences in the total brain volumes of gray or white matter for the three subject groups ( p > 0.23). Comparison of the total ALS group and controls revealed localized deficits in gray matter volume centered on Brodmann areas 8, 9, and 10 bilaterally. Comparison of the patients with limb- and bulbar-onset ALS revealed deficits in the white matter volume in the bulbar-onset group, extending bilaterally from the precentral gyrus into the internal capsule and brainstem, consistent with the course of the corticospinal tract. There was no loss in gray matter volume in the precentral gyri. Conclusions: The loss of gray matter in the frontal regions (total ALS group) provides further support that ALS is a multisystem disorder. In addition, there is in vivo evidence of axonal degeneration in the subcortical white matter in the motor region in patients with bulbar-onset ALS. This is consistent with a “dying back” process affecting cortical motoneurons in bulbar-onset ALS.

The motor cortex and amyotrophic lateral sclerosis.

Abstract: On theoretical grounds, abnormalities of the motor cortex in patients with amyotrophic lateral sclerosis (ALS) could lead to anterograde ("dying-forward") transneuronal degeneration of the anterior horn cells as suggested by Charcot. Conversely, retrograde ("dying-back") degeneration of the corticospinal tracts could affect the motor cortex. Evidence derived from clinical, neuropathological, static, and functional imaging, and physiological studies, favors the occurrence of anterograde degeneration. It is hypothesized that transneuronal degeneration in ALS is an active excitotoxic process in which live but dysfunctional corticomotoneurons, originating in the primary motor cortex, drive the anterior horn cell into metabolic deficit. When this is marked, it will result in more rapid and widespread loss of lower motor neurons. In contrast, slow loss of corticomotoneurons, as occurs in primary lateral sclerosis (PLS), precludes excitotoxic drive and is incompatible with anterograde degeneration. Preservation of slow-conducting non-M1 direct pathways in PLS is not associated with excitotoxicity, and anterior horn cells survive for long periods of time.

Apoptosis in amyotrophic lateral sclerosis: a review of the evidence.

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting the upper and lower motor neurones of the central nervous system. Recently, a lot of interest has been generated by the possibility that a mechanism of programmed cell death, termed apoptosis, is responsible for the motor neurone degeneration in this condition. Apoptosis is regulated through a variety of different pathways which interact and eventually lead to controlled cell death. Apart from genetic regulation, factors involved in the control of apoptosis include death receptors, caspases, Bcl-2 family of oncoproteins, inhibitor of apoptosis proteins (IAPs), inhibitors of IAPs, the p53 tumour suppressor protein and apoptosis-related molecules. The first part of this article will give an overview of the current knowledge of apoptosis. In the second part of this review, we will examine in detail the evidence for and against the contribution of apoptosis in motor neurone cell death in ALS, looking at cellular-, animal- and human post-mortem tissue-based models. In a chronic neurodegenerative disease such as ALS, conclusive evidence of apoptosis is likely to be difficult to detect, given the rapidity of the apoptotic cell death process in relation to the relatively slow time course of the disease. Although a complete picture of motor neurone death in ALS has not been fully elucidated, there is good and compelling evidence that a programmed cell death pathway operates in this disorder. The strongest body of evidence supporting this comes from the findings that, in ALS, changes in the levels of members of the Bcl-2 family of oncoproteins results in a predisposition towards apoptosis, there is increased expression or activation of caspases-1 and -3, and the dying motor neurones in human cases exhibit morphological features reminiscent of apoptosis. Further supporting evidence comes from the detection of apoptosis-related molecules and anti-Fas receptor antibodies in human cases of ALS. However, the role of the p53 protein in cell death in ALS is at present unclear. An understanding of the mechanism of programmed cell death in ALS may provide important clues for areas of potential therapeutic intervention for neuroprotection in this devastating condition.

Marked increase in cyclooxygenase-2 in ALS spinal cord: implications for therapy.

Abstract: Objective: To evaluate the hypothesis that cyclooxygenase-2 (COX-2) is linked to the pathology of ALS by determining whether COX-2 mRNA levels are upregulated in ALS spinal cord. Methods: Spinal cord from 11 ALS cases and 27 controls consisting of 15 cases of Alzheimer disease (AD), six cases of Parkinson disease (PD), three cases of cerebrovascular disease, and three control cases were analyzed. Total RNA was extracted and reverse transcriptase-PCR analysis performed for the mRNA of COX-2 , COX-1 , the microglial marker CD11b , and the housekeeping gene cyclophilin . Results: In ALS compared with non-ALS spinal cord, COX-2 mRNA was upregulated 7.09-fold ( p COX-1 1.14-fold ( p = 0.05), and CD11b 1.85-fold ( p = 0.0012). COX-2 mRNA levels in AD, PD, cerebrovascular disease, and control cases were each significantly lower than in ALS and were not significantly different from each other. Western blots of the protein products were in general accord with the mRNA data, with COX-2 protein levels being upregulated 3.79-fold compared with non-ALS cases ( p = 0.015). Conclusions: The strong upregulation of COX-2 mRNA in ALS is in accord with studies in the superoxide dismutase transgenic mouse model in which COX-2 upregulation occurs. Taken in conjunction with evidence of a neuroprotective effect of COX-2 inhibitors in certain animal models and in organotypic cultures, the data are supportive of a possible future role for COX-2 inhibitors in the treatment of ALS.

Does primary lateral sclerosis exist? A study of 20 patients and a review of the literature.

Abstract: The question of whether primary lateral sclerosis (PLS) is a nosological entity distinct from amyotrophic lateral sclerosis (ALS) has been the subject of controversy since it was first described in the nineteenth century. PLS has been defined as a rare, non-hereditary disease characterized by progressive spinobulbar spasticity, related to the selective loss of precentral pyramidal neurones, with secondary pyramidal tract degeneration and preservation of anterior horn motor neurones. In the recent clinical literature, the frontier between ALS and neurodegenerative disease remains poorly defined. We studied 20 patients with a diagnosis of PLS. We carried out a variety of tests in order to determine the presence of a more diffuse neurodegenerative process. We also performed a longitudinal electrophysiological evaluation. Our clinical, electrophysiological and pathological investigations provide evidence that the disease has a heterogeneous clinical presentation and that degeneration is not restricted to the central motor system.

Cognitive impairment in sporadic ALS: a pathologic continuum underlying a multisystem disorder.

Abstract: Background: Traditionally considered a motor neuron–selective disorder, the clinical manifestations of ALS can include a frontotemporal dementia. Although the pathologic substrate of cognitive impairment remains to be defined, the presence of ubiquitin-immunoreactive (Ub+) intraneuronal inclusions in cortical regions has been suggested to constitute a pathologic marker of this process. Methods: The authors compared the neuropathological features of four cognitively impaired patients with ALS, four cognitively intact patients with ALS, and four neurologically normal patients. The extent and load of Ub+ neuronal inclusions, Ub+ dystrophic neurites, and superficial linear spongiosis (SLS) was determined among a number of cortical, hippocampal, and subcortical regions. Results: Although Ub+, alpha-synuclein-negative, and tau-negative neuronal inclusions were observed in both cognitively impaired and cognitively intact patients with ALS, their density and extent was greater among the former, with the difference greatest in the cingulate gyrus. Ub+ neurites were observed in a similar distribution. Only the presence of SLS, affecting the first and second cortical layers, reliably distinguished between the cognitively impaired and cognitively intact ALS subpopulations. In three of four cognitively impaired patients with ALS, SLS was associated with transcortical microglial activation, in the absence of detectable differences in astrocytosis, density of calbindin or parvalbumin neurons, or optical density of synaptophysin and SNAP-25. Conclusions: Although intraneuronal Ub+ inclusions and dystrophic neurites are observed in both ALS subpopulations, the presence of cognitive impairment was associated with a greater distribution and load of both neuropathologic features, suggesting a disease continuum. Moreover, cognitive impairment was uniformly associated with superficial linear spongiosis, a pathologic feature common to several forms of frontotemporal dementia.

Disease mechanisms revealed by transcription profiling in SOD1-G93A transgenic mouse spinal cord.

Abstract: Mutations of copper,zinc-superoxide dismutase (cu,zn SOD) are found in patients with a familial form of amyotrophic lateral sclerosis. When expressed in transgenic mice, mutant human cu,zn SOD causes progressive loss of motor neurons with consequent paralysis and death. Expression profiling of gene expression in SOD1-G93A transgenic mouse spinal cords indicates extensive glial activation coincident with the onset of paralysis at 3 months of age. This is followed by activation of genes involved in metal ion regulation (metallothionein-I, metallothionein-III, ferritin-H, and ferritin-L) at 4 months of age just prior to end-stage disease, perhaps as an adaptive response to the mitochondrial destruction caused by the mutant protein. Induction of ferritin-H and -L gene expression may also limit iron catalyzed hydroxyl radical formation and consequent oxidative damage to lipids, proteins, and nucleic acids. Thus, glial activation and adaptive responses to metal ion dysregulation are features of disease in this transgenic model of familial amyotrophic lateral sclerosis.

Reversible ALS-like disorder in HIV infection.

Abstract: Objective: To describe the clinical features, treatment, and outcome of six cases of HIV-1-associated ALS-like disorder. Methods: The authors reviewed patients with HIV infection with neurologic symptoms seen over a 13-year period. Patients were identified by using the El Escorial research diagnostic criteria defining three categories of certainty for definite, probable, or possible ALS. Clinical features, EMG, CSF, serum analyses, and imaging and virological studies were assessed. Results: Six patients with immunodepression (mean CD4 + cells = 86.2/mm 3 ; mean age = 34 years) developed distal motor weakness mimicking a monomelic amyotrophy that subacutely progressed regionally or assumed a symmetric distribution on more than one region. EMG was characteristic of motor neuron disease with no multifocal conduction block. Causes other than HIV-1 were ruled out. The unusual rapid extension of the disease and the positive response to antiretroviral therapy suggest that ALS syndrome and HIV infection are etiologically related. HIV-1 might cause an ALS-like disorder by several mechanisms—via neuronal infection, by secretion of toxic viral substance, by inducing the immune system to secrete cytokines, or by inducing an autoimmune disease. Conclusion: These cases suggest that the association between some motor neuron diseases and HIV infection is not coincidental but pathogenetically related and that ALS-like disorder should be considered an HIV-related neurologic complication.

Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS

Abstract: Background: Spinal muscular atrophy (SMA) results from mutations of the survival motor neuron (SMN) gene on chromosome 5. The SMN gene exists in two highly homologous copies, telomeric (SMN1) and centromeric (SMN2). SMA is caused by mutations in SMN1 but not SMN2. The clinical phenotype of SMA appears to be related to the expression of SMN2. Patients suffering from the milder forms of SMA carry more copies of the SMN2 gene compared with patients with more severe SMA. It is suggested that the SMN2 gene is translated into an at least partially functional protein that protects against loss of motor neurons. Objective: To investigate whether genetic mechanisms implicated in motor neuron death in SMA have a role in ALS. Methods: The presence of deletions of exons 7 and 8 of SMN1 and SMN2 was determined in 110 patients with sporadic ALS and compared with 100 unaffected controls. Results: The presence of a homozygous SMN2 deletion was overrepresented in patients with ALS compared with controls (16% versus 4%; OR, 4.4; 95% CI, 1.4 to 13.5). Patients with a homozygous SMN2 deletion had a shorter median time of survival ( p p Conclusion: These results indicate that, similar to SMA, the SMN2 gene can act as a prognostic factor and may therefore be a phenotypic modifier in sporadic ALS. Increasing the expression of the SMN2 gene may provide a strategy for treatment of motor neuron disease.

Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation.

Abstract: Familial amyotrophic lateral sclerosis (ALS) with mutations in the gene for superoxide dismutase-1 (SOD1) is clinicopathologically reproduced by transgenic mice expressing mutant forms of SOD1 detectable in familial ALS patients. Motor neuron degeneration associated with SOD1 mutation has been thought to result from a novel neurotoxicity of mutant SOD1, but not from a reduction in activity of this enzyme, based on autosomal dominant transmission of SOD1 mutant familial ALS and its transgenic mouse model, clinical severity of the ALS patients independent to enzyme activity, no ALS-like disease in SOD1 knockout or wild-type SOD1-overexpressing mice, and clinicopathological severity of mutant SOD1 transgenic mice dependent on transgene copy numbers. Proposed mechanisms of motor neuron degeneration such as oxidative injury, peroxynitrite toxicity, cytoskeletal disorganization, glutamate excitotoxicity, disrupted calcium homeostasis, SOD1 aggregation, carbonyl stress and apoptosis have been discussed. Intracytoplasmic vacuoles, indicative of increased oxidative damage to the mitochondria and endoplasmic reticulum, in the neuropil and motor neurons appear in high expressors of mutant SOD1 transgenic mice but not in low expressors of the mice or familial ALS patients, suggesting that overexpression of mutant SOD1 in mice may enhance oxidative stress generation from this enzyme. Thus, transgenic mice carrying small transgene copy numbers of mutant SOD1 would provide a beneficial animal model for SOD1 mutant familial ALS. Such a model would contribute to elucidating the pathomechanism of this disease and establishing new therapeutic agents.

A potential role for the p75 low-affinity neurotrophin receptor in spinal motor neuron degeneration in murine and human amyotrophic lateral sclerosis.

Abstract: INTRODUCTION: The p75 neurotrophin receptor has been recognized as a death-signalling molecule under certain circumstances. Its role in motor neuron degeneration in amyotrophic lateral sclerosis (ALS) was analysed in SOD1-G93A transgenic mice and in spinal cords from human amyotrophic lateral sclerosis. METHOD: The precise loss of motor neurons in SOD1-G93A transgenic mice from birth to adulthood was established using the unbiased fractionator/optical dissector neuronal counting technique. RESULTS: This study showed an early trend in the loss of lumbar motor neurons in SOD1-G93A mice, beginning at birth and progressing to a massive 80% reduction by 4 months of age, when the disease is severe. This study also found that the p75 neurotrophin receptor was expressed in lumbar motor neurons in symptomatic SOD1-G93A mice and in motor neurons in the cervical spinal cords of patients with ALS. CONCLUSIONS: The murine and human ALS data suggest that the p75 neurotrophin receptor may play a death-signalling role in...