Mouse models of amyotrophic lateral sclerosis
2
Citation
76
Reference
10
Related Paper
Citation Trend
Abstract Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in amyotrophic lateral sclerosis cases, and clearly differentiated all forms of amyotrophic lateral sclerosis from controls. Substantial heterogeneity in the presence of these changes was also observed between amyotrophic lateral sclerosis cases. Our data demonstrate that varying forms of SOD1 proteinopathy are a common feature of all forms of amyotrophic lateral sclerosis, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in amyotrophic lateral sclerosis. Most of these alterations are specific to regions of neurodegeneration, and may therefore constitute valid targets for therapeutic development.
Cite
Citations (46)
Dismutase
Muscle Atrophy
Cite
Citations (40)
The identification of patients with amyotrophic lateral sclerosis (ALS) within a single family, some with SOD1 mutation, and some without, complicates the genetic counselling and understanding of ALS.
Mutations in the gene for copper/zinc superoxide dismutase (SOD1) were first identified in patients with familial ALS in 1993.1 Since then, 153 different mutations have been reported. A substantial body of research has developed, in particular around the transgenic mouse models based on these human mutations.2 Despite the potential promise of determining the pathogenesis and treatment of ALS, progress from the clinical point of …
Pathogenesis
Dismutase
Cite
Citations (2)
Abstract 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. Ann Neurol 2007;61:427–434
Pathogenesis
Cite
Citations (923)
Superoxide dismutases(SOD)are known as biological cleaning agents of free radicals in vivo,and Cu,Zn-SOD also called SOD1,is one of the main forms.SOD1 mutations have been linked fatal human motor neuron diseases,such as amyotrophic lateral sclerosis,ALS.However,the precise roles of SOD1 in ALS occurenace and progression remianed unknown.This review will focus on the mechanism of SOD1's activation based on the structural conformation analysis of SOD1 and the copper chaperone for SOD1(CCS).Meanwhile,the latest research progresses of the possible pathogenic mechanisms in ALS will also be discussed.
Dismutase
Chaperone (clinical)
Cite
Citations (0)
Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disorder.Mutations in the Cu,Zn-superoxide dismutase(SOD1)gene cause ALS by an unknown gain-of-function mechanism.Current researches show that diminishing SOD1 mutation enzymatic activity does not account for motor neuron lose in ALS,while direct toxicity of variant SOD1 protein or aggregation of SOD1 protein may impart cell function and cause motor neuron death.Though motor neuron death is selective,other cells also participate in this course.The author reviewed recent advances in the relationship between mutant SOD1 and Amyotrophic Lateral Sclerosis.
Gain of function
Cite
Citations (0)
Riluzole
Cite
Citations (187)
Dear Sir,Mutations in Cu/Zn superoxide dismutase (SOD1; OMIM 147450) are the first discovered genetic defect linked to amyotrophic lateral sclerosis (ALS) (1). Mutant SOD1 induces non-cell-autonomo...
Dismutase
Cite
Citations (5)
Abstract The demonstration of a genetic linkage between the copper‐zinc superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis has aroused interest in the role of SOD1 in motoneuronal death. We investigated the expression of the human SOD1 gene at a cellular level in the motoneurons of patints with sporadic amytrophic lateral sclerosis, patients with familial amyotrophic lateral sclerosis, and normal control subjects, using a quantitative insitu hybridization technique. There were no significant differences between the amountf os SOD1 messenger RNA observed in patints wtih sporadic disease, patients with familial disease, and normal control subjects. However, many of the atrophic motoneurons from patients with sporadic or familial disease had significantly lower levls of SOD1 messenger RNA, compared to morphologically intact motoneurons. Moreover, motoneurons in the normal spinal ventral horn and precentral motor cortex exhibited significantly higher levels of SOD1 messenger RNA than did other neurons. Our study indicated that vulnerable neurons in amyotrophic lateral sclerosis exhibit high levels of SOD1 messenger RNA, suggesting a close relatioship between the SOD1 gene and the pathogenesisof amyotrophic lateral sclerosis.
Cite
Citations (6)
Mutations in the gene superoxide dismutase 1 (SOD1) are causative for familial forms of the neurodegenerative disease amyotrophic lateral sclerosis. When the first SOD1 mutations were identified they were postulated to give rise to amyotrophic lateral sclerosis through a loss of function mechanism, but experimental data soon showed that the disease arises from a—still unknown—toxic gain of function, and the possibility that loss of function plays a role in amyotrophic lateral sclerosis pathogenesis was abandoned. Although loss of function is not causative for amyotrophic lateral sclerosis, here we re-examine two decades of evidence regarding whether loss of function may play a modifying role in SOD1–amyotrophic lateral sclerosis. From analysing published data from patients with SOD1–amyotrophic lateral sclerosis, we find a marked loss of SOD1 enzyme activity arising from almost all mutations. We continue to examine functional data from all Sod1 knockout mice and we find obvious detrimental effects within the nervous system with, interestingly, some specificity for the motor system. Here, we bring together historical and recent experimental findings to conclude that there is a possibility that SOD1 loss of function may play a modifying role in amyotrophic lateral sclerosis. This likelihood has implications for some current therapies aimed at knocking down the level of mutant protein in patients with SOD1–amyotrophic lateral sclerosis. Finally, the wide-ranging phenotypes that result from loss of function indicate that SOD1 gene sequences should be screened in diseases other than amyotrophic lateral sclerosis.
Loss function
Cite
Citations (290)