Peripheral and Central Glutamate Dyshomeostasis in Neurodegenerative Disorders

Onaolapo, Adejoke Yetunde; Onaolapo, Olakunle James

doi:10.2174/1570159x18666201015161919

Cited by 16 publications

(9 citation statements)

References 286 publications

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“…et al, 2005; Bahi-Buisson et al, 2008; Chan et al, 2019) a clinical condition that also occurs in ADGRV1-associated epilepsy (Leng et al, 2022). Overall, our results suggest that ADGRV1 is significantly involved in the control of glutamate homeostasis, which is imbalanced by defects in ADGRV1, which is proven to be disease relevant (Onaolapo and Onaolapo, 2020).…”

Section: Discussionmentioning

confidence: 77%

The adhesion GPCR ADGRV1 controls glutamate homeostasis in hippocampal astrocytes supporting neuron development: first insights into to pathophysiology ofADGRV1-associated epilepsy

Güler,

Zorin,

Linnert

et al. 2024

Preprint

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ADGRV1 is the largest member of adhesion G protein-coupled receptor (aGPCR) family. In the cell, aGPCRs have dual roles in cell adhesion and signal transduction. Mutations in ADGRV1 have been linked not only to Usher syndrome (USH), which causes deaf-blindness, but recently also to various forms of epilepsy. While the USH defects are attributed to the loss of fiber links between membranes formed by the extracellular domain of ADGRV1, the pathomechanisms leading to epilepsy remain elusive to date. Here, we study the specific functions of ADGRV1 in astrocytes where it is highest expressed in the nervous system. Affinity proteomics showed the interaction of ADRGV1 with proteins enriched in astrocytes. Dysregulations of cellular processes important in astrocyte function were indicated by the different transcriptomes of patient-derived cells and Adgrv1-deficent mouse hippocampi compared to appropriate controls. Alteration in morphology and reduced numbers of astrocytes in the hippocampus of Adgrv1-deficent mice. Monitoring the glutamate uptake in colorimetric assay and by live cell imaging of a genetic glutamate reporter consistently showed that glutamate uptake from the extracellular environment is significantly reduced in Adgrv1-deficent astrocytes. Expression analyses of key enzymes of the glutamate-glutamine cycle in astrocytes and the glutamate metabolism indicated imbalanced glutamate homeostasis in Adgrv1-deficient astrocytes. Finally, we provide evidence that the supportive function of astrocytes in neuronal development also relies on ADGRV1 expression in astrocytes. Our data collectively provides first insights into the molecular pathophysiology underlying the development of epilepsy associated with mutations in ADGRV1.

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Section: Discussionmentioning

confidence: 77%

The adhesion GPCR ADGRV1 controls glutamate homeostasis in hippocampal astrocytes supporting neuron development: first insights into to pathophysiology ofADGRV1-associated epilepsy

Güler,

Zorin,

Linnert

et al. 2024

Preprint

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“…GPX4 can increase peroxidase activity, reduce the toxicity of lipid peroxides, and maintain the cell membrane lipid bilayer stability, finally inhibit ferroptosis ( Koppula et al, 2018 ).When xc − system function is damaged or intracellular cysteine is inadequate, GSH synthesis decreases, causing ferroptosis. Glutamate is one of the most important amino acids in the body and plays a crucial role in the nervous system ( Onaolapo and Onaolapo, 2021 ). Its reduction may be associated closely with intracellular cystine starvation, which results in ferroptosis ( Figure 3 ).…”

Section: Metabolic Mechanisms Of Ferroptosismentioning

confidence: 99%

Ferroptosis: a new regulatory mechanism in neuropathic pain

Li,

Guo,

Gao

et al. 2023

Front. Aging Neurosci.

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Neuropathic pain (NP) is pain caused by damage to the somatosensory system. It is a common progressive neurodegenerative disease that usually presents with clinical features such as spontaneous pain, touch-evoked pain, nociceptive hyperalgesia, and sensory abnormalities. Due to the complexity of the mechanism, NP often persists. In addition to the traditionally recognized mechanisms of peripheral nerve damage and central sensitization, excessive iron accumulation, oxidative stress, neuronal inflammation, and lipid peroxidation damage are distinctive features of NP in pathophysiology. However, the mechanisms linking these pathological features to NP are not fully understood. The complexity of the pathogenesis of NP greatly limits the development of therapeutic approaches for NP. Ferroptosis is a novel form of cell death discovered in recent years, in which cell death is usually accompanied by massive iron accumulation and lipid peroxidation. Ferroptosis-inducing factors can affect glutathione peroxidase directly or indirectly through different pathways, leading to decreased antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. It has been shown that ferroptosis is closely related to the pathophysiological process of many neurological disorders such as NP. Possible mechanisms involved are changes in intracellular iron ion levels, alteration of glutamate excitability, and the onset of oxidative stress. However, the functional changes and specific molecular mechanisms of ferroptosis during this process still need to be further explored. How to intervene in the development of NP by regulating cellular ferroptosis has become a hot issue in etiological research and treatment. In this review, we systematically summarize the recent progress of ferroptosis research in NP, to provide a reference for further understanding of its pathogenesis and propose new targets for treatment.

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“…Furthermore, the liver modulates the concentration of glutamate, a prominent neuromodulator (responsible for neuronal synaptoplasticity) and neurotransmitter [ 14 , 158 ]. The potential involvement of peripheral (liver)/central glutamate homeostasis in the development of neurodegenerative disorders has been recently reviewed by Oanolapo et al [ 159 ]. It was also demonstrated that the liver adipose tissue secretes several proinflammatory factors, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), which play a role in inducing systemic insulin resistance.…”

Section: Ad As Insulinopathymentioning

confidence: 99%

Imaging Methods Applicable in the Diagnostics of Alzheimer’s Disease, Considering the Involvement of Insulin Resistance

Hnilicová

Kantorová

Šutovský

et al. 2023

IJMS

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Alzheimer’s disease (AD) is an incurable neurodegenerative disease and the most frequently diagnosed type of dementia, characterized by (1) perturbed cerebral perfusion, vasculature, and cortical metabolism; (2) induced proinflammatory processes; and (3) the aggregation of amyloid beta and hyperphosphorylated Tau proteins. Subclinical AD changes are commonly detectable by using radiological and nuclear neuroimaging methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Furthermore, other valuable modalities exist (in particular, structural volumetric, diffusion, perfusion, functional, and metabolic magnetic resonance methods) that can advance the diagnostic algorithm of AD and our understanding of its pathogenesis. Recently, new insights into AD pathoetiology revealed that deranged insulin homeostasis in the brain may play a role in the onset and progression of the disease. AD-related brain insulin resistance is closely linked to systemic insulin homeostasis disorders caused by pancreas and/or liver dysfunction. Indeed, in recent studies, linkages between the development and onset of AD and the liver and/or pancreas have been established. Aside from standard radiological and nuclear neuroimaging methods and clinically fewer common methods of magnetic resonance, this article also discusses the use of new suggestive non-neuronal imaging modalities to assess AD-associated structural changes in the liver and pancreas. Studying these changes might be of great clinical importance because of their possible involvement in AD pathogenesis during the prodromal phase of the disease.

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Peripheral and Central Glutamate Dyshomeostasis in Neurodegenerative Disorders

Cited by 16 publications

References 286 publications

The adhesion GPCR ADGRV1 controls glutamate homeostasis in hippocampal astrocytes supporting neuron development: first insights into to pathophysiology ofADGRV1-associated epilepsy

The adhesion GPCR ADGRV1 controls glutamate homeostasis in hippocampal astrocytes supporting neuron development: first insights into to pathophysiology ofADGRV1-associated epilepsy

Ferroptosis: a new regulatory mechanism in neuropathic pain

Imaging Methods Applicable in the Diagnostics of Alzheimer’s Disease, Considering the Involvement of Insulin Resistance

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