Parkinson's disease and glutamate excitotoxicity

Mironova, Yu. S.; Жукова, И. А.; Жукова, Н. Г.; Алифирова, В. М.; Izhboldina, O.; Латыпова, А. В.

doi:10.17116/jnevro201811806250

Cited by 25 publications

(11 citation statements)

References 28 publications

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“…Additionally, glutamate and arginine are precursors to the formation of proline, so the metabolic pathway that promotes glutamate by arginine also further increases glutamate accumulation (31). In this study, these two enriched pathways may have indirectly caused an elevation in the concentration of glutamate and L-proline in the gut of PD patients, which is consistent with previous finding of PD disease (32). Glutamate functions as an excitatory neurotransmitter and can cause an excitatory response when it binds to its receptor, so the extracellular concentration of glutamate should remain low to maintain a healthy state (8).…”

Section: Discussionsupporting

confidence: 89%

Altered Actinobacteria and Firmicutes Phylum Associated Epitopes in Patients With Parkinson’s Disease

Lü

et al. 2021

Front. Immunol.

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Recent evidence suggests that inflammation was participated in the pathogenesis of PD, thus, to understand the potential mechanism of gut microbiota in the pathogenesis of Parkinson’s disease (PD), we performed a metagenomic analysis of fecal samples from PD patient and controls. Using a two-stage metagenome-wide association strategy, fecal DNA samples from 69 PD patients and 244 controls in three groups (comprising 66 spouses, 97 age-matched, and 81 normal samples, respectively) were analyzed, and differences between candidate gut microbiota and microbiota-associated epitopes (MEs) were compared. In the study, 27 candidate bacterial biomarkers and twenty-eight candidate epitope peptides were significantly different between the PD patients and control groups. Further, enriched 4 and 13 MEs in PD were positively associated with abnormal inflammatory indicators [neutrophil percentage (NEUT.1), monocyte count/percentage (MONO/MONO.1), white blood cell count (WBC)] and five candidate bacterial biomarkers (c_Actinobacteria, f_Bifidobacteriaceae, g_Bifidobacterium, o_Bifidobacteriales, p_Actinobacteria) from Actinobacteria phylum, and they were also positively associated with histidine degradation and proline biosynthesis pathways, respectively. Additionally, enriched 2 MEs and 1 ME in PD were positively associated with above inflammatory indicators and two bacteria (f_Lactobacillaceae, g_Lactobacillus) from Firmicutes phylum, and they were also positively associated with pyruvate fermentation to propanoate I and negatively associated with isopropanol biosynthesis, respectively. Of these MEs, two MEs from GROEL2, RPSC were derived from Mycobacterium tuberculosis, triggered the T cell immune response, as previously reported. Additionally, other candidate epitope peptides derived from Mycobacterium tuberculosis and Mycobacterium leprae may also have potential immune effects in PD. In all, the altered MEs in PD may relate to abnormalities in immunity and glutamate and propionate metabolism, which furthers our understanding of the pathogenesis of PD.

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Section: Discussionsupporting

confidence: 89%

Altered Actinobacteria and Firmicutes Phylum Associated Epitopes in Patients With Parkinson’s Disease

Lü

et al. 2021

Front. Immunol.

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“…GLT-1 up-regulation was critical for protective effects of ginsenoside Rb1 on dopaminergic cells against MPTP-induced injury in mice (88). There is also mounting evidence supporting the important role of glutamate transporters in the glutamatergic excitotoxicity seen in PD patients (89,90). Moreover, higher astrocytic GLT-1 expression was correlated with the improved cognitive function in human subjects with AD pathogenesis (91), underscoring the role of GLT-1 in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte-specific deletion of the transcription factor Yin Yang 1 in murine substantia nigra mitigates manganese-induced dopaminergic neurotoxicity

Pajarillo

Johnson

Rizor

et al. 2020

Journal of Biological Chemistry

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Manganese (Mn)-induced neurotoxicity resembles Parkinson’s disease (PD), but the mechanisms underpinning its effects remain unknown. Mn dysregulates astrocytic glutamate transporters, GLT-1 and GLAST, and dopaminergic function, including tyrosine hydroxylase (TH). Our previous in vitro studies have shown that Mn repressed GLAST and GLT-1 via activation of transcription factor Yin Yang 1 (YY1). Here, we investigated if in vivo astrocytic YY1 deletion mitigates Mn-induced dopaminergic neurotoxicity, attenuating Mn-induced reduction in GLAST/GLT-1 expression in murine substantia nigra (SN). AAV5-GFAP-Cre-GFP particles were infused into the SN of 8-week old YY1flox/floxmice to generate a region-specific astrocytic YY1 conditional knockout (cKO) mouse model. Three weeks after AAV infusion, mice were exposed to 330 μg Mn (MnCl2 30 mg/kg, intranasal instillation, daily) for 3 weeks. After Mn exposure, motor functions were determined in open-field and rotarod tests, followed by western blot, qPCR and immunohistochemistry to assess YY1, TH, GLAST and GLT-1 levels. Infusion of AAV5-GFAP-Cre-GFP vectors into the SN resulted in region-specific astrocytic YY1 deletion and attenuation of Mn-induced (1) impairment of motor functions, (2) reduction of TH-expressing cells in SN and TH mRNA/protein levels in midbrain/striatum. Astrocytic YY1 deletion also attenuated the Mn-induced decrease in GLAST/GLT-1 mRNA/protein levels in midbrain. Moreover, YY1 deletion abrogated its interaction with HDACs in astrocytes. These results indicate that astrocytic YY1 plays a critical role in Mn-induced neurotoxicity in vivo, at least in part, by reducing astrocytic GLAST/GLT-1. Thus, YY1 might be a potential target for treatment of Mn toxicity and other neurological disorders associated with dysregulation of GLAST/GLT-1.

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“…Another obvious pathway for retinal damage during ALS may be an increase in glutamatergic transmission. 127,128 The involvement of glutamate, its receptors and transporters in neuronal death has been found in many neurodegenerative processes, including ALS, 129 Parkinson's disease, 130,131 Alzheimer's disease, [132][133][134] dementia with Lewy bodies 132 and Huntington's disease. 135 Interestingly, the only drug that prolongs survival of ALS patients is riluzole, the glutamate neurotransmission blocker.…”

Section: Excitotoxicitymentioning

confidence: 99%

Retinal Damage in Amyotrophic Lateral Sclerosis: Underlying Mechanisms

Солдатов

Kukharsky

Белых

et al. 2021

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in a gradual loss of motor neuron function. Although ophthalmic complaints are not presently considered a classic symptom of ALS, retinal changes such as thinning, axonal degeneration and inclusion bodies have been found in many patients. Retinal abnormalities observed in postmortem human tissues and animal models are similar to spinal cord changes in ALS. These findings are not dramatically unexpected because retina shares an ontogenetic relationship with the brain, and many genes are associated both with neurodegeneration and retinal diseases. Experimental studies have demonstrated that ALS affects many "vulnerable points" of the retina. Aggregate deposition, impaired nuclear protein import, endoplasmic reticulum stress, glutamate excitotoxicity, vascular regression, and mitochondrial dysfunction are factors suspected as being the main cause of motor neuron damage in ALS. Herein, we show that all of these pathways can affect retinal cells in the same way as motor neurons. Furthermore, we suppose that understanding the patterns of neuro-ophthalmic interaction in ALS can help in the diagnosis and treatment of this disease.

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Parkinson's disease and glutamate excitotoxicity

Cited by 25 publications

References 28 publications

Altered Actinobacteria and Firmicutes Phylum Associated Epitopes in Patients With Parkinson’s Disease

Altered Actinobacteria and Firmicutes Phylum Associated Epitopes in Patients With Parkinson’s Disease

Astrocyte-specific deletion of the transcription factor Yin Yang 1 in murine substantia nigra mitigates manganese-induced dopaminergic neurotoxicity

Retinal Damage in Amyotrophic Lateral Sclerosis: Underlying Mechanisms

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