Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients

Donnenfeld, Hyman; Kascsak, Richard J.; Bartfeld, Harry

doi:10.1016/0165-5728(84)90042-0

Cited by 114 publications

(72 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…C1q is a secreted, extracellular polypeptide which can bind antibody aggregates and is the main initiating factor for the classic complement pathway which is used to clear/lyse (antibody-marked) debris, pathogens and injured or degenerating cells (23). Complement activation has been associated with several neurodegenerative diseases, including ALS, Parkinson's and Alzheimer's (31)(32)(33)(34)(35) and analysis of entire spinal cords from mutant SOD1 G93A mice showed transcriptional up-regulation of complement components at early symptomatic stages (10). C1q components have also previously been suggested to be produced by injured or stressed neurons, especially in Alzheimer's disease (36)(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Lobsiger

Boillée

Cleveland

2007

Proc. Natl. Acad. Sci. U.S.A.

134

133

View full text Add to dashboard Cite

Global, age-dependent changes in gene expression from rodent models of inherited ALS caused by dominant mutations in superoxide-dismutase 1 (SOD1) were identified by using gene arrays and RNAs isolated from purified embryonic and adult motor neurons. Comparison of embryonic motor neurons expressing a dismutase active ALS-linked mutant SOD1 with those expressing comparable levels of wild-type SOD1 revealed the absence of mutant-induced mRNA changes. An age-dependent mRNA change that developed presymptomatically in adult motor neurons collected by laser microdissection from mice expressing dismutase active ALS-linked mutants was dysregulation of the D/L-serine biosynthetic pathway, previously linked to both excitotoxic and neurotrophic effects. An unexpected dysregulation common to motor neurons expressing either dismutase active or inactive mutants was induction of neuronally derived components of the classic complement system and the regenerative/injury response. Alteration of these mutant SOD1-induced pathways identified a set of targets for therapies for inherited ALS.amyotrophic lateral sclerosis ͉ gene expression profile ͉ laser microdissection A myotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disease that selectively kills brain and spinal cord motor neurons (reviewed in ref. 1). Although most ALS cases are sporadic and of unknown origin, some familial instances are caused by acquired toxic properties of dominant missense point mutations in the ubiquitously expressed superoxide dismutase 1 (SOD1) independent of its dismutase activity (2, 3). Because both familial and sporadic forms lead to what is nearly indistinguishable diseases, the analysis of mutant (human or mouse) SOD1-overexpressing rodent ALS models, which develop a fatal, late-onset, progressive ALS-like paralysis (4-7), can provide valuable tools for dissecting the overall ALS disease mechanism.The central question in understanding ALS in mutant SOD1-expressing mouse and rat models is what are the slowly acting toxic mechanisms, or build-up of toxic products that are responsible for ultimately leading to the degeneration of the most at-risk cell type, the large spinal cord motor neurons (1). Such properties of mutant SOD1 seem likely to induce responses in the genes expressed by motor neurons (their transcriptome) at early disease stages or even before obvious clinical symptoms. Identifying the manner in which motor neurons respond to, or are affected by, ALS-linked mutant SOD1-induced damage could provide key insights either into primary mechanisms of toxicity or to potential therapeutic approaches that may be successful in slowing disease progression in ALS.High-density oligonucleotide microarrays provide an excellent tool to test on a genome wide level the effects of candidate events on the cellular expression profile. Because certain aspects of ALS are non-cell autonomous and originate from mutant SOD1 accumulation in non-motor neuronal cells (8, 9), cell-type specificity is of high importance when using such an a...

show abstract

Section: Discussionmentioning

confidence: 99%

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Lobsiger

Boillée

Cleveland

2007

Proc. Natl. Acad. Sci. U.S.A.

134

133

View full text Add to dashboard Cite

show abstract

“…Analyses of postmortem tissues of ALS patients (both SALS and FALS) also indicated the evidence of blood-spinal cord barrier impairment including endothelial cell damage, pericyte degeneration, and reduced TJ protein expression. [12][13][14][15] However, it still has to be elucidated if the barrier damage is an initial disease factor and which molecular mechanisms trigger the barrier disruption.…”

Section: Introductionmentioning

confidence: 99%

Expression of the ALS-Causing Variant hSOD1^G93A Leads to an Impaired Integrity and Altered Regulation of Claudin-5 Expression in an in Vitro Blood–Spinal Cord Barrier Model

Meister

Storck

Hameister

et al. 2015

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to the loss of primary and secondary motor neurons. Mutations in the Cu/Zn-superoxide dismutase (SOD1) gene are associated with familial ALS and to date numerous hypotheses for ALS pathology exist including impairment of the blood-spinal cord barrier. In transgenic mice carrying mutated SOD1 genes, a disrupted blood-spinal cord barrier as well as decreased levels of tight junction (TJ) proteins ZO-1, occludin, and claudin-5 were detected. Here, we examined TJ protein levels and barrier function of primary blood-spinal cord barrier endothelial cells of presymptomatic hSOD1 G93A mice and bEnd.3 cells stably expressing hSOD1 G93A . In both cellular systems, we observed reduced claudin-5 levels and a decreased transendothelial resistance (TER) as well as an increased apparent permeability. Analysis of the β-catenin/AKT/forkhead box protein O1 (FoxO1) pathway and the FoxO1-regulated activity of the claudin-5 promoter revealed a repression of the claudin-5 gene expression in hSOD1 G93A cells, which was depended on the phosphorylation status of FoxO1. These results strongly indicate that mutated SOD1 affects the expression and localization of TJ proteins leading to impaired integrity and breakdown of the blood-spinal cord barrier.

show abstract

“…These include macrophages and mast cells [73] and also T cells in the areas of motor neuron destruction [63,74,75]. There is evidence of immunoglobulin deposition in the CNS in ALS [76] and also of complement deposition [63,77].…”

Section: Studies In Humansmentioning

confidence: 99%

The Role of Immune and Inflammatory Mechanisms in ALS

McCombe¹,

Henderson²

2011

CMM

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease. The cause is unknown, but genetic abnormalities have been identified in subjects with familial ALS and also in subjects with sporadic ALS. Environmental factors such as occupational exposure have been shown to be risk factors for the development of ALS. Patients differ in their clinical features and differ in the clinical course of disease. Immune abnormalities have been found in the central nervous system by pathological studies and also in the blood and CSF of subjects with ALS. Inflammation and immune abnormalities are also found in animals with a model of ALS due to mutations in the SOD1 gene. Previously it has been considered that immune abnormalities might contribute to the pathogenesis of disease. However more recently it has become apparent that an immune response can occur as a response to damage to the nervous system and this can be protective.

show abstract

Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients

Cited by 114 publications

References 3 publications

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Expression of the ALS-Causing Variant hSOD1^G93A Leads to an Impaired Integrity and Altered Regulation of Claudin-5 Expression in an in Vitro Blood–Spinal Cord Barrier Model

The Role of Immune and Inflammatory Mechanisms in ALS

Contact Info

Product

Resources

About

Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients

Cited by 114 publications

References 3 publications

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Expression of the ALS-Causing Variant hSOD1G93A Leads to an Impaired Integrity and Altered Regulation of Claudin-5 Expression in an in Vitro Blood–Spinal Cord Barrier Model

The Role of Immune and Inflammatory Mechanisms in ALS

Contact Info

Product

Resources

About

Expression of the ALS-Causing Variant hSOD1^G93A Leads to an Impaired Integrity and Altered Regulation of Claudin-5 Expression in an in Vitro Blood–Spinal Cord Barrier Model