Common polymorphisms of <i>chemokine (C‐X3‐C motif) receptor 1</i> gene modify amyotrophic lateral sclerosis outcome: A population‐based study

Calvo, Andrea; Moglia, Cristina; Canosa, Antonio; Cammarosano, Stefania; Ilardi, Antonio; Bertuzzo, Davide; Traynor, Bryan J.; Brunetti, Maura; Barberis, Marco; Mora, Gabriele; Casale, Federico; Chiò, Adriano

doi:10.1002/mus.25653

Cited by 24 publications

(12 citation statements)

References 33 publications

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“…This finding directly contradicts a study performed on a much smaller population of individuals, where the presence of V249I was associated with shorter survival [ 114 , 115 ]. Thus, it is obvious that larger cohorts of patients should be enrolled in studies to properly determine the effect of gene polymorphisms on ALS.…”

Section: Cx3cl1/cx3cr1 Signaling In Neurodegenerative Diseasescontrasting

confidence: 67%

The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders

Pawelec

Ziemka‐Nałęcz

Sypecka

et al. 2020

Cells

135

116

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Fractalkine (FKN, CX3CL1) is a transmembrane chemokine expressed by neurons in the central nervous system (CNS). CX3CL1 signals through its unique receptor, CX3CR1, that is expressed in microglia. Within the CNS, fractalkine acts as a regulator of microglia activation in response to brain injury or inflammation. During the last decade, there has been a growing interest in the roles that the CX3CL1/CX3CR1 signaling pathway plays in the neuropathology of a diverse array of brain disorders. However, the reported results have proven controversial, indicating that a disruption of the CX3CL1 axis induces a disease-specific microglial response that may have either beneficial or detrimental effects. Therefore, it has become clear that the understanding of neuron-to-glia signals mediated by CX3CL1/CX3CR1 at different stages of diseases could provide new insight into potential therapeutic targets. Hence, the aim of this review is to provide a summary of the literature on the emerging role of CX3CL1 in animal models of some brain disorders.

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Section: Cx3cl1/cx3cr1 Signaling In Neurodegenerative Diseasescontrasting

confidence: 67%

The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders

Pawelec

Ziemka‐Nałęcz

Sypecka

et al. 2020

Cells

135

116

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“…There is no GWAS tag-SNP associated with the CX3CR1 (chemokine (C-X3-C motif) receptor 1) gene. Whereas, recently, it was reported that the V249I and T280M polymorphisms of the CX3CR1 gene are associated with the risk of ALS and modify phenotype in a large population-based series of ALS patients 20 . To explore the potential function of CX3CR1 in the brain, we explored CX3CR1 expression in different cell types of the central nervous system using the data from 21 .…”

Section: Resultsmentioning

confidence: 97%

Functional fine-mapping of noncoding risk variants in amyotrophic lateral sclerosis utilizing convolutional neural network

Yousefian-Jazi

Sung

Lee

et al. 2020

Sci Rep

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Recent large-scale genome-wide association studies have identified common genetic variations that may contribute to the risk of amyotrophic lateral sclerosis (ALS). However, pinpointing the risk variants in noncoding regions and underlying biological mechanisms remains a major challenge. Here, we constructed a convolutional neural network model with a large-scale GWAS meta-analysis dataset to unravel functional noncoding variants associated with ALS based on their epigenetic features. After filtering and prioritizing of candidates, we fine-mapped two new risk variants, rs2370964 and rs3093720, on chromosome 3 and 17, respectively. Further analysis revealed that these polymorphisms are associated with the expression level of CX3CR1 and TNFAIP1, and affect the transcription factor binding sites for CTCF, NFATc1 and NR3C1. Our results may provide new insights for ALS pathogenesis, and the proposed research methodology can be applied for other complex diseases as well.

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“…In the mSOD1 G93A mouse model of ALS, Cx3cr1 −/− mice showed more neuronal loss than Cx3cr1 +/− or Cx3cr1 +/+ mice, indicating a gene-dosage neuroprotective effect 128 . In support of this role, the loss of function of Cx3cr1 seen with the V249I rs3732379 Cx3cr1 variant was associated with accelerated progression and reduced survival in some ALS patients 131 , but not in others 132 . In both studies, Cx3cr1 variants did not increase risk for ALS.…”

Section: Cx3cr1–fractalkinementioning

confidence: 90%

Microglia in neurodegeneration

et al. 2018

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The neuroimmune system is involved in development, normal functioning, aging, and injury of the central nervous system. Microglia, first described a century ago, are the main neuroimmune cells and have three essential functions: a sentinel function involved in constant sensing of changes in their environment, a housekeeping function that promotes neuronal well-being and normal operation, and a defense function necessary for responding to such changes and providing neuroprotection. Microglia use a defined armamentarium of genes to perform these tasks. In response to specific stimuli, or with neuroinflammation, microglia also have the capacity to damage and kill neurons. Injury to neurons in Alzheimer's, Parkinson's, Huntington's, and prion diseases, as well as in amyotrophic lateral sclerosis, frontotemporal dementia, and chronic traumatic encephalopathy, results from disruption of the sentinel or housekeeping functions and dysregulation of the defense function and neuroinflammation. Pathways associated with such injury include several sensing and housekeeping pathways, such as the Trem2, Cx3cr1 and progranulin pathways, which act as immune checkpoints to keep the microglial inflammatory response under control, and the scavenger receptor pathways, which promote clearance of injurious stimuli. Peripheral interference from systemic inflammation or the gut microbiome can also alter progression of such injury. Initiation or exacerbation of neurodegeneration results from an imbalance between these microglial functions; correcting such imbalance may be a potential mode for therapy.

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Common polymorphisms of chemokine (C‐X3‐C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population‐based study

Abstract: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57: 212-216, 2018.

Cited by 24 publications

References 33 publications

The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders

The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders

Functional fine-mapping of noncoding risk variants in amyotrophic lateral sclerosis utilizing convolutional neural network

Microglia in neurodegeneration

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