Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson’s disease

Goldknopf, Ira L.; Sheta, Eman; Bryson, Jennifer; Folsom, Brian; Wilson, Chris; Duty, Jeff; Yen, Albert; Appel, Stanley H.

doi:10.1016/j.bbrc.2006.02.051

Cited by 116 publications

(84 citation statements)

References 51 publications

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“…Differential expression of complement proteins may represent potentially useful BMs for amyotrophic lateral sclerosis and PD. 79 These findings lend further support to evidence suggesting that inflammatory processes involving complement cascade elements may be involved in the onset of PD.…”

Section: Fig 2 Pre-diagnostic Phase Of Parkinson's Disease (Pd)supporting

confidence: 72%

Biomarkers for Evaluation of Clinical Efficacy of Multipotential Neuroprotective Drugs for Alzheimer's and Parkinson's Diseases

et al. 2009

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Summary: During the last century, the world population has shown a staggering increase in its proportion of elderly members and thus neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), respectively, are becoming an increasing burden on society. Among the diverse, significant challenges facing clinicians, is the improvement of diagnostic measures to detect early and subtle symptoms, a phase in which prevention efforts might be expected to have their greatest impact and provide a measure of disease progression that can be evaluated during the course of drug treatment. At present, clinical diagnosis of AD and PD is based on a constellation of symptoms and manifestations, although the disease originated several years earlier. Given the multiple etiological nature of AD and PD, it is reasonable to assume that the initial causative pathobiological processes may differ between the affected individuals. Therefore, the availability of biological markers or biomarkers will help not only early disease diagnosis, but also delineate the pathological mechanisms more definitively and reliably than the traditional cognitive and neurological phenotypes. In the current article, we review the literature on biochemical, genetic, and neuroimaging biomarkers and discuss their predictive value as indicative for disease vulnerability to detect individuals at risk for PD and AD, and to determine the clinical efficacy of novel, disease-modifying (neuroprotective) strategies.

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Section: Fig 2 Pre-diagnostic Phase Of Parkinson's Disease (Pd)supporting

confidence: 72%

Biomarkers for Evaluation of Clinical Efficacy of Multipotential Neuroprotective Drugs for Alzheimer's and Parkinson's Diseases

et al. 2009

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“…Although the pathogenesis of this condition is poorly understood, there is persuasive evidence that complement factors are involved (5)(6)(7)(8)(9). Given that C1q mRNA expression is significantly increased in mouse models of ALS (13-15), we sought to determine the involvement of complement factors in the rat SOD1 G93A transgenic model of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…The classical complement system is also implicated in ALS pathophysiology. Activation fragments of the complement components C3 and C4 are increased in the serum and cerebrospinal fluid of ALS patients (5)(6)(7). Elevated levels of these fragments are also localized to glia in the spinal cord and motor cortex of ALS patients (6,8).…”

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confidence: 99%

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

Woodruff¹,

Costantini²,

Crane

et al. 2008

The Journal of Immunology

141

177

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Complement activation products are elevated in the cerebrospinal fluid and spinal cord of patients with amyotrophic lateral sclerosis (ALS). In this study, we demonstrate complement system involvement in a rodent model of ALS (human SOD1G93A transgenic rats). With end-stage disease, SOD1G93A rats displayed marked deposition of C3/C3b, and a significant up-regulation of the C5aR in the lumbar spinal cord. This was associated with increased numbers of C5aR-positive astrocytes. However, expression of C5L2, the alternative receptor for C5a, was highest on motor neurons early in the disease process. To determine the contribution of C5a to the pathology displayed by this model of ALS, rats were administered an orally active, selective C5aR antagonist (PMX205; 1 mg/kg/day, oral). Animals treated with PMX205 displayed a significant extension of survival time and a reduction in end-stage motor scores, as compared with vehicle-treated rats. PMX205-treated animals also displayed reduced levels of astroglial proliferation in the lumbar spinal cord. This study provides the first demonstration of an involvement of C5a in an ALS model and suggests that inhibitors of complement activation could be beneficial in the treatment of this neurodegenerative disease.

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“…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.

133

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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...

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Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson’s disease

Cited by 116 publications

References 51 publications

Biomarkers for Evaluation of Clinical Efficacy of Multipotential Neuroprotective Drugs for Alzheimer's and Parkinson's Diseases

Biomarkers for Evaluation of Clinical Efficacy of Multipotential Neuroprotective Drugs for Alzheimer's and Parkinson's Diseases

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

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

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