Connexin 30 Deficiency Ameliorates Disease Progression at the Early Phase in a Mouse Model of Amyotrophic Lateral Sclerosis by Suppressing Glial Inflammation

Hashimoto, Yu; Yamasaki, Ryo; Ko, Senri; Matsuo, Eisuke; Kobayakawa, Yoshitaka; Kitajima, Masaki; Matsuse, Dai; Isobe, Noriko

doi:10.3390/ijms232416046

Cited by 5 publications

(5 citation statements)

References 86 publications

(104 reference statements)

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“…Astrocyte activation was reduced in Cx30KO-mSOD1 mice compared with that in mSOD1 mice. Furthermore, the expression of Cx 43 in the pre-onset stage was downregulated in Cx30KO-mSOD1 mice, suggesting that the reduced expression of astroglial Cx30 in the early disease stage in ALS model mice protects neurons by attenuating astroglial inflammation [84].…”

Section: Motor Neuron Diseasementioning

confidence: 98%

Connexins Control Glial Inflammation in Various Neurological Diseases

Yamasaki

2023

IJMS

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Connexins (Cxs) form gap junctions through homotypic/heterotypic oligomerization. Cxs are initially synthesized in the endoplasmic reticulum, then assembled as hexamers in the Golgi apparatus before being integrated into the cell membrane as hemichannels. These hemichannels remain closed until they combine to create gap junctions, directly connecting neighboring cells. Changes in the intracellular or extracellular environment are believed to trigger the opening of hemichannels, creating a passage between the inside and outside of the cell. The size of the channel pore depends on the Cx isoform and cellular context-specific effects such as posttranslational modifications. Hemichannels allow various bioactive molecules, under ~1 kDa, to move in and out of the host cell in the direction of the electrochemical gradient. In this review, we explore the fundamental roles of Cxs and their clinical implications in various neurological dysfunctions, including hereditary diseases, ischemic brain disorders, degenerative conditions, demyelinating disorders, and psychiatric illnesses. The influence of Cxs on the pathomechanisms of different neurological disorders varies depending on the circumstances. Hemichannels are hypothesized to contribute to proinflammatory effects by releasing ATP, adenosine, glutamate, and other bioactive molecules, leading to neuroglial inflammation. Modulating Cxs’ hemichannels has emerged as a promising therapeutic approach.

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Section: Motor Neuron Diseasementioning

confidence: 98%

Connexins Control Glial Inflammation in Various Neurological Diseases

Yamasaki

2023

IJMS

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“…Cx30 deficiency increased microglia ramifications enlarged astrocytic processes, and reduced Cx43 expression [280,281]. Recent findings suggest, using a genetic approach that reduced expression of astroglial Cx30 in SOD1 G93A mice protects neurons at the early disease stage by attenuating astroglial inflammation [282] and, similarly, reducing Cx43 expression improved disease progression [283]. Further evidence confirming the importance of hemichannels in ALS has been proposed by Lehrer and collaborators, pointing out that insulin can block Cx31 and Cx43, inhibiting the release of toxic molecules, including glutamate, thus representing a potential pharmacological intervention for ALS [284].…”

Section: Hemichannelsmentioning

confidence: 99%

The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity

Provenzano,

Torazza,

Bonifacino

et al. 2023

IJMS

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In the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the “astrocytic signature” in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release. Since glutamate excitotoxicity is one of the most relevant ALS features, we focused on the specific contribution of ALS astrocytes in this aspect, highlighting the known or potential molecular mechanisms by which astrocytes participate in increasing the extracellular glutamate level in ALS and, conversely, undergo the toxic effect of the excessive glutamate. In this scenario, astrocytes can behave as “producers” and “targets” of the high extracellular glutamate levels, going through changes that can affect themselves and, in turn, the neuronal and non-neuronal surrounding cells, thus actively impacting the ALS course. Moreover, this review aims to point out knowledge gaps that deserve further investigation.

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“…ALS, as a multifactorial, multisystem neuroinflammatory disorder, leads to compromised muscle function and eventual mortality. The onset and progression of ALS coincide with alterations in inflammatory proteins, while neuroinflammation further hastens disease progression and exacerbates its severity; however, peripheral inflammatory processes remain insufficiently characterized [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association analysis reveals potential genetic correlation and causality between circulating inflammatory proteins and amyotrophic lateral sclerosis

Shen,

Gu,

Xiao

et al. 2024

Aging

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Background: Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease, continues to elude complete comprehension of its pathological underpinnings. Recent focus on inflammation in ALS pathogenesis prompts this investigation into the genetic correlation and potential causal relationships between circulating inflammatory proteins and ALS. Methods: Genome-wide association study (GWAS) data encompassing 91 circulating inflammatory protein measures from 14,824 individuals of European ancestry, alongside records from 27,205 ALS cases and 110,881 controls, were employed. Assessment of genetic correlation and overlap utilized LD score regression (LDSC), high-definition likelihood (HDL), and genetic analysis integrating pleiotropy and annotation (GPA) methodologies. Identification of shared genetic loci involved pleiotropy analysis, functional mapping and annotation (FUMA), and co-localization analysis. Finally, Mendelian randomization was applied to probe causal relationships between inflammatory proteins and ALS. Results: Our investigation revealed significant genetic correlation and overlap between ALS and various inflammatory proteins, including C-C motif chemokine 28, Interleukin-18, C-X-C motif chemokine 1, and Leukemia inhibitory factor receptor (LIFR). Pleiotropy analysis uncovered shared variations at specific genetic loci, some of which bore potential harm. Mendelian randomization analysis suggested that alterations in specific inflammatory protein levels, notably LIFR, could impact ALS risk. Conclusions: Our findings uncover a genetic correlation between certain circulating inflammatory proteins and ALS, suggesting their possible causal involvement in ALS pathogenesis. Moreover, the identification of LIFR as a crucial protein may yield new insights into ALS pathomechanisms and offer a promising avenue for therapeutic interventions. These discoveries provide novel perspectives for advancing the comprehension of ALS pathophysiology and exploring potential therapeutic avenues.

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Connexin 30 Deficiency Ameliorates Disease Progression at the Early Phase in a Mouse Model of Amyotrophic Lateral Sclerosis by Suppressing Glial Inflammation

Cited by 5 publications

References 86 publications

Connexins Control Glial Inflammation in Various Neurological Diseases

Connexins Control Glial Inflammation in Various Neurological Diseases

The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity

Genome-wide association analysis reveals potential genetic correlation and causality between circulating inflammatory proteins and amyotrophic lateral sclerosis

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