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Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS); however, a comprehensive examination of complement expression in this disease has not been performed. This study therefore aimed to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5 and C...
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Context 1
... hSOD1 G93A mice carry a high copy number of the mutated allele of the human (h) SOD1 gene. Female hSOD1 G93A and WT mice at four predefined stages of ALS were used in this study (Table 1). By the end stage of ALS, hSOD1 G93A mice display significant signs of hind- limb weakness, paralysis and loss of the righting reflex. ...
Similar publications
Objective:
The neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is a heterogeneous clinical syndrome involving multiple molecular pathways. The development of biomarkers for use in therapeutic trials is a priority. We sought to use a high-throughput proteomic method to identify novel biomarkers in individual cerebrospinal fluid (CSF...
Citations
... Multiple other studies showed higher-thannormal levels of C3 and C4 in the serum of patients with ALS [65][66][67]. Some studies also showed an increased expression of C5a Receptor 1 (C5aRl) and reduced expression of Decay Accelerating Factor (DAF) and CD59, a membrane attack complex inhibitor [68,69]. Thus, complement-driven therapeutics are one of the crosswalks to consider while discussing emerging therapies for ALS. ...
Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease affecting the motor neurons. Although the etiology remains unknown, mutations in superoxide dismutase 1 have been observed in patients with familial ALS, resulting in increased calcium in the cells and leading to cell death. Additionally, studies in patients with the C9orf72 repeat expansion have shown lower age of onset, cognitive and behavioral impairments, and reduced survival. Accumulation of TDP-43 in the cytoplasm of neurons and glial cells caused by the loss of UBQLN2 has been shown to lead to mitotoxicity and proteasomal overload. Early diagnosis of ALS is necessary for the optimization of care between a patient’s neurologist and interdisciplinary team members to ensure the best outcomes possible. Proper management between physical therapy, occupation therapy, and pharmaceutical medications can improve ALS symptoms, achieving the highest quality of life possible for the patient. The current therapeutic medication recommended for ALS is Riluzole, but new therapies are emerging. This paper analyzes mechanisms of injury and progression of ALS along while analyzing current, emerging, and alternative therapeutics targeting ALS.
... Multiple other studies showed higher-than-normal levels of C3 and C4 in the serum of patients with ALS [65][66][67]. Some studies also showed an increased expression of C5a Receptor 1 (C5aR1) and reduced expression of Decay Accelerating Factor (DAF) and CD59, a membrane attack complex inhibitor [68,69]. Thus, complement-driven therapeutics are one of the crosswalks to consider while discussing emerging therapies for ALS. ...
Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease affecting the motor neurons. Although the etiology remains unknown, mutations in superoxide dis-mutase 1 have been observed in patients with familial ALS, resulting in increased calcium in the cells and leading to cell death. Additionally, studies in patients with the C9orf72 repeat expansion have shown lower age of onset, cognitive and behavioral impairments, and reduced survival. Accumulation of TDP-43 in the cytoplasm of neurons and glial cells caused by the loss of UBQLN2 has been shown to lead to mitotoxicity and proteasomal overload. Early diagnosis of ALS is necessary for the optimization of care between a patient's neurolo-gist and interdisciplinary team members to ensure the best outcomes possible. Proper management between physical therapy, occupation therapy, and pharmaceutical medications can improve ALS symptoms, achieving the highest quality of life possible for the patient. The current therapeutic medication recommended for ALS is Riluzole, but new therapies are emerging. This paper analyzes mechanisms of injury and progression of ALS along while analyzing current, emerging, and alternative therapeutics targeting ALS.
... Research has shown that during aging, microglial cells in the human brain undergo cellular senescence, impairing their proliferative response to challenges (Hua et al. 2012). This diminished capacity for specific microglial responses results in a preference for the pro-inflammatory phenotype over the anti-inflammatory phenotype (Lee et al. 2013). Therefore, the increasing inflammation in the aging brain and microglial senescence are likely interconnected phenomena. ...
Microglia, the resident immune cells of the central nervous system, play a critical role in maintaining brain homeostasis. However, in neurodegenerative conditions, microglial cells undergo metabolic reprogramming in response to pathological stimuli, including Aβ plaques, Tau tangles, and α-synuclein aggregates. This metabolic shift is characterized by a transition from oxidative phosphorylation (OXPHOS) to glycolysis, increased glucose uptake, enhanced production of lactate, lipids, and succinate, and upregulation of glycolytic enzymes. These metabolic adaptations result in altered microglial functions, such as amplified inflammatory responses and diminished phagocytic capacity, which exacerbate neurodegeneration. This review highlights recent advances in understanding the molecular mechanisms underlying microglial metabolic reprogramming in neurodegenerative diseases and discusses potential therapeutic strategies targeting microglial metabolism to mitigate neuroinflammation and promote brain health.
Graphical Abstract
Microglial Metabolic Reprogramming in Neurodegenerative Diseases
This graphical abstract illustrates the metabolic shift in microglial cells in response to pathological stimuli and highlights potential therapeutic strategies targeting microglial metabolism for improved brain health.
... A total of 8 µL (4 µL/point) of AAV-DX2 was slowly injected (1 µL/min) with a Hamilton syringe (Hamilton, Switzerland) at two points while the needle was slowly retracted to prevent loss of injected virus. We injected AAV-DX2 at the asymptomatic stage of the SOD1 animals [49]. Injections were performed by an investigator blinded to each group. ...
Although a couple of studies have reported that mutant superoxide dismutase 1 (SOD1), one of the causative genes of familial amyotrophic lateral, interacts physically with lysyl-tRNA synthetase (KARS1) by a gain of function, there is limited evidence regarding the detailed mechanism about how the interaction leads to neuronal cell death. Our results indicated that the aminoacyl-tRNA synthetase-interacting multi-functional protein 2 (AIMP2) mediated cell death upon the interplay between mutant SOD1 and KARS1 in ALS. Binding of mutant SOD1 with KARS1 led to the release of AIMP2 from its original binding partner KARS1, and the free form of AIMP2 induced TRAF2 degradation followed by TNF-α-induced cell death. We also suggest a therapeutic application that overexpression of DX2, the exon 2-deleted antagonistic splicing variant of AIMP2 (AIMP2-DX2), reduced neuronal cell death in the ALS mouse model. Expression of DX2 suppressed TRAF2 degradation and TNF-α-induced cell death by competing mode of action against full-length AIMP2. Motor neuron differentiated form iPSC showed a resistance in neuronal cell death after DX2 administration. Further, intrathecal administration of DX2-coding adeno-associated virus (AAV) improved locomotive activity and survival in a mutant SOD1-induced ALS mouse model. Taken together, these results indicated that DX2 could prolong life span and delay the ALS symptoms through compensation in neuronal inflammation.
... According to the defined disease stages of the transgenic SOD1 models of ALS, an age of 70-130 days after birth is considered the onset of the disease, where the initial signs of motor deficiency are observed. The end-stage of the disease originates after 150 days of postnatal age and is associated with full paralysis of the lower limbs (Lee et al. 2013). ...
Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neurons that mainly affects the motor cortex, brainstem, and spinal cord. Under disease conditions, microglia could possess two distinct profiles, M1 (toxic) and M2 (protective), with the M2 profile observed at disease onset. SOD1 (superoxide dismutase 1) gene mutations account for up to 20% of familial ALS cases. Comparative gene expression differences in M2-protective (early) stage SOD1G93A microglia and age-matched SOD1G93A motor neurons are poorly understood. We evaluated the differential gene expression profiles in SOD1G93A microglia and SOD1G93A motor neurons utilizing publicly available transcriptomics data and bioinformatics analyses, constructed biomolecular networks around them, and identified gene clusters as potential drug targets. Following a drug repositioning strategy, 5 small compounds (belinostat, auranofin, BRD-K78930611, AZD-8055, and COT-10b) were repositioned as potential ALS therapeutic candidates that mimic the protective state of microglia and reverse the toxic state of motor neurons. We anticipate that this study will provide new insights into the ALS pathophysiology linking the M2 state of microglia and drug repositioning.
... Apart from C1q and C3, terminal complement proteins are beginning to attract research interests. Altered expression of complement components is observed in the spinal cord during the progression of ALS, including upregulation of C1qB, C4, factor B, C3/C3b, C5, and especially C5aR, and a decrease in CD55, CD59, with most of these changes occurring in the vicinity of microglia [77]. Similar to C1q and C3, C4 and MAC accumulate in the spinal cord and motor cortex of ALS human samples, along with reactive gliosis and peripheral immune cell infiltration [49]. ...
The functions of the complement system to both innate and adaptive immunity through opsonization, cell lysis, and inflammatory activities are well known. In contrast, the role of complement in the central nervous system (CNS) which extends beyond immunity, is only beginning to be recognized as important to neurodevelopment and neurodegeneration. In addition to protecting the brain against invasive pathogens, appropriate activation of the complement system is pivotal to the maintenance of normal brain function. Moreover, overactivation or dysregulation may cause synaptic dysfunction and promote excessive pro-inflammatory responses. Recent studies have provided insights into the various responses of complement components in different neurological diseases and the regulatory mechanisms involved in their pathophysiology, as well as a glimpse into targeting complement factors as a potential therapeutic modality. However, there remain significant knowledge gaps in the relationship between the complement system and different brain disorders. This review summarizes recent key findings regarding the role of different components of the complement system in health and pathology of the CNS and discusses the therapeutic potential of anti-complement strategies for the treatment of neurodegenerative conditions.
... Lee et al. showed in hSOD1G93A mice increased immunolabelling for C3b in the lumbar spinal cords. Moreover, C3b deposition appeared primarily on motor neurons and microglia [13]. ...
... As has already been stated above, the complement C3/C3b was found in the intercostal muscle at the motor nerve terminal and terminal Schwann cells [10]. In the animal study dysregulation of the complement system at pre-symptomatic stage was shown [13]. Although the role of complement in ALS pathophysiology becomes more apparent, still there is a shortage of research in this particular field. ...
... Studies in the SOD1(G93A) mouse suggest that activation of complement via C1q and C3b deposition at the motor end-plate precedes neurodegeneration [10]. Hence, reducing complement-induced inflammation could be an important therapeutic strategy to treat ALS [13]. Alterations in complement proteins in CSF were predominantly statistically insignificant. ...
ALS remains a fatal, neurodegenerative motor neuron disease. Numerous studies seem to confirm that innate immune system is involved in the pathophysiology of ALS. Hence, the assessment of the complement system and attempts to modify its activity remain the target of medical intervention in ALS. In the present study, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin–) cells were performed every 6 weeks in 20 sporadic ALS patients. The concentrations of various complement components in the cerebrospinal fluid and plasma at different time points after cell injection were quantified using a Luminex multiplex. The results of the complement system were correlated with the level of leukocytes, neutrophils, lymphocytes, fibrinogen and CRP in the peripheral blood and the functional status of ALS patients using Norris and ALS-FRSr scales. The study showed a statistically significant decrease in plasma C3b concentration in all 7th days after cell application. In parallel, a peak decrease in neutrophil count and CRP level was observed on days 5–7, with a simultaneous maximum clinical improvement on days 7–28 of each Lin– cell administration. Adjuvant Lin– cell therapy appears to have the silencing potential on the complement-mediated immune system and thus suppress pro-inflammatory reactions responsible for neurodegeneration. However, further in-depth studies are necessary to address this issue.
... A substantial body of research has been performed on ALS patients and animal models of ALS, investigating the levels of complement components in the blood, motor cortex, spinal cord, and skeletal muscle [80][81][82][83][84][85]. Although the majority of these studies have focussed on complement activation in the circulation and central nervous system, there are now emerging studies that have investigated complement in skeletal muscle ALS pathology. ...
The complement cascade is a key arm of the immune system that protects the host from exogenous and endogenous toxic stimuli through its ability to potently regulate inflammation, phagocytosis, and cell lysis. Due to recent clinical trial successes and drug approvals for complement inhibitors, there is a resurgence in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several diseases. In particular, neuromuscular diseases are undergoing a recent focus, with demonstrated links between complement activation and disease pathology. This review aims to provide a comprehensive overview of complement activation and its role during the initiation and progression of neuromuscular disorders including myasthenia gravis, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy. We will review the preclinical and clinical evidence for complement in these diseases, with an emphasis on the complement-targeting drugs in clinical trials for these indications.
... C1QB is also an important part of the complement C1Q. The studies of Wang et al. and Lee et al. showed that C1QB was upregulated in tibialis anterior muscles of amyotrophic sclerosis (ALS) mouse and increased the disease progression through complement induction verification (26,27). In the research of Byrnes, adult male rats were used to construct model of spinal cord injury (SCI), and found that inflammation-related genes were long-term upregulated in the SCI model by using microarray analysis and protein expression (28). ...
Objective
Idiopathic short stature (ISS), an endocrine-related disease, is difficult to diagnose. Previous studies have shown that many children with some inflammation-related diseases often have short stature, but whether inflammation is the underlying mechanism of ISS has not been studied. Here, we attempt to explore the role of inflammation in the occurrence and development of ISS and to demonstrate an available clinical diagnostic model of ISS.
Methods
Frozen serum samples were collected from ISS patients (n = 4) and control individuals (n = 4). Isobaric tags for relative and absolute quantitation (iTRAQ) combined with LC-MS/MS analysis were applied to quantitative proteomics analysis. To assess clusters of potentially interacting proteins, functional enrichment (GO and KEGG) and protein-protein interaction network analyses were performed, and the crucial proteins were detected by Molecular Complex Detection (MCODE). Furthermore, serum levels of two selected proteins were measured by ELISA between ISS patients (n = 80) and controls (n = 80). In addition, experiments in vitro were used to further explore the effects of crucial proteins on endochondral ossification.
Results
A total of 437 proteins were quantified, and 84 DEPs (60 upregulated and 24 downregulated) were identified between patients with ISS and controls. Functional enrichment analysis showed that the DEPs were primarily enriched in blood microparticle, acute inflammatory response, protein activation cascade, collagen-containing extracellular matrix, platelet degranulation, etc. According to the results of top 10 fold change DEPs and MCODE analysis, C1QA and C1QB were selected to further experiment. The expression levels of C1QA and C1QB were validated in serum samples. Based on the logistic regression analysis and ROC curve analysis, we constructed a novel diagnostic model by serum levels of C1QA and C1QB with a specificity of 91.2% and a sensitivity of 75% (AUC = 0.900, p <0.001). Finally, the western blotting analysis confirmed the expression levels of OCN, OPN, RUNX2, and Collagen X were downregulated in chondrocytes, and the outcome of Collagen II was upregulated.
Conclusion
Our study is the first to demonstrate the significant role of inflammation in the development of ISS. In addition, we identify C1QA and C1QB as novel serum biomarkers for the diagnosis of ISS.
... In addition, levels of complement inhibitors DAF (CD55) and protectin (CD59) were altered at the endplates of motor neurons in ALS patients (96). The role of complement in ALS was also supported by the findings that in mouse models of ALS, genetic or pharmacologic inhibition of C5aR1 delayed disease progression (91,92,94), and that complement inhibitors DAF (CD55) and protectin (CD59) were downregulated in ALS mouse models (97,98). C3 and C3aR are also increased in the brain of AD patients as well as in the mouse brain of an AD model (99). ...
... However, in the context of neuronal toxicity, the lytic function of the TPCC is suspected to be the primary cause of neuronal cell death. This is the case in a variety of neurological disorders including stroke (107)(108)(109)(110), traumatic brain injury (TBI) (111)(112)(113), spinal cord injury (114)(115)(116), ALS (92,94,(96)(97)(98)117), and neuropathic pain (7). ...
... This increased deposition of TPCC in various neuropathologies is likely driven by poor regulation of the formation and insertion of the complex. Indeed, the ubiquitously expressed inhibitor of TPCC formation, protectin (CD59), is downregulated in ALS patients (97,98), and its genetic knockout impairs recovery in rodent models of stroke (110) and spinal cord injury (115). Although these various pathologies are defined by different types of neurological trauma or neurodegeneration, a common hallmark of these diseases is the contribution of excessive TPCC activity to neuronal death, due to either excessive activation of the TPCC or dysregulation of the inhibitory mechanisms ( Figure 2). ...
The complement cascade is a key component of the innate immune system that is rapidly recruited through a cascade of enzymatic reactions to enable the recognition and clearance of pathogens and promote tissue repair. Despite its well understood role in immunology, recent studies have highlighted new and unexpected roles of the complement cascade in neuro-immune interaction and in the regulation of neuronal processes during development, aging, and in disease states. Complement signaling is particularly important in directing neuronal responses to tissue injury, neurotrauma, and nerve lesions. Under physiological conditions, complement-dependent changes in neuronal excitability, synaptic strength, and neurite remodeling promote nerve regeneration, tissue repair, and healing. However, in a variety of pathologies, dysregulation of the complement cascade leads to chronic inflammation, persistent pain, and neural dysfunction. This review describes recent advances in our understanding of the multifaceted cross-communication that takes place between the complement system and neurons. In particular, we focus on the molecular and cellular mechanisms through which complement signaling regulates neuronal excitability and synaptic plasticity in the nociceptive pathways involved in pain processing in both health and disease. Finally, we discuss the future of this rapidly growing field and what we believe to be the significant knowledge gaps that need to be addressed.
