Roles of Glutamate Receptors in Parkinson’s Disease

Zhang, Zhu; Zhang, Shiqing; Fu, Pengfei; Zhang, Zhang; Lin, Kaili; Ko, Jae-Ki; Yung, Kin Lam

doi:10.3390/ijms20184391

Cited by 109 publications

(84 citation statements)

References 120 publications

(120 reference statements)

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“…Table S3 presents the top 10 out of the 50 identified significantly altered pathways in the 3M HET mice versus the 3M WT mice. Top pathways altered are related to serotonin and glutamate neurotransmissions, which are known to regulate firing activity of SN dopaminergic neurons [66,107]. Interestingly, a pathway related to G-protein-coupled receptor (GPCR) signaling ("G-protein signaling -Regulation of Cyclic AMP levels by ACM") was identified.…”

Section: Pathway and Gene Set Analysismentioning

confidence: 99%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

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Understanding Parkinson's disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles from α-synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD. 1/30 models provide a useful means to investigate PD-associated molecular changes, in particular those preceding nigro-striatal degeneration. The elucidation of such early changes can shed light into disease causation and drivers of disease progression, thus in turn pointing to novel targets for intervention as well as biomarkers [16,45].Whole transcriptome analysis enables to compare thousands of genes between two or more groups [9], and provides a valuable method for identifying coordinated changes in gene expression patterns that are not captured by single-gene or protein measurement approaches [59]. Despite of these advantages, only a limited amount of studies have used transcriptomics on α-synuclein-based transgenic mouse models for PD [13, 67, 71-73, 94, 98]. Alpha-synuclein, a pre-synaptic protein believed to be a moderator of the synaptic vesicle cycle, is a major component of Lewy bodies [87]. In addition, mutations or multiplications in its genes leads to familiar forms of PD [26,46]. Transcriptomics studies on α-synuclein-based transgenic mouse models for PD have only looked at differentially expressed genes (DEGs) in relation to pre-defined cellular pathways or gene sets from public annotation databases [13,67,[71][72][73]94]. Most of them used only one [71][72][73] or two age groups [13,67,94,98] of the mouse model for their analyses, and some of them were perform...

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Section: Pathway and Gene Set Analysismentioning

confidence: 99%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

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“…Taurine has many important physiological functions, which include an important role in the modulation of several neurotransmitter systems [mainly glutamatergic and GABAergic; specifically chronic supplementation of taurine increases glutamate and GABA concentrations and glutamate decarboxylase (GAD) activity and induces modifications in the expression of certain subtypes of N-methyl-D-aspartate (NMDA) glutamate receptors and GABA A receptors], in the modulation of mitochondrial function and in intracellular calcium homeostasis, and is a potent anti-oxidant [50]. Glutamate has an important role in the pathophysiology of PD due to its actions as an excitatory neurotransmitter (participating in the disruption of the normal basal ganglia function and in the mechanisms leading to neuronal death) and the presence of changes in many types of glutamate receptors described in PD patients [51]. It was hypothesized that CSF taurine concentrations should be decreased as a consequence of the oxidative stress processes in PD [52], that CSF glutamate concentrations should be decreased because of the decrease of CSF taurine levels found in this meta-analysis and, according to Tohgi et al [27], that this decrease may reflect impairments of the neural function and protein synthesis in the nigrostriatal and other neuronal systems.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal and blood levels of amino acids as potential biomarkers for Parkinson’s disease: review and meta‐analysis

Jiménez‐Jiménez

Alonso‐Navarro

García‐Martín

et al. 2020

Euro J of Neurology

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Background and purpose: The present systematic review and meta-analysis aims to establish the possible value of cerebrospinal fluid (CSF) and serum/plasma levels of amino acids as markers of Parkinson's disease (PD). Methods: This is a review of four databases (PubMed, Embase, MED-LINE and Web of Science-Core Collection) from 1966 to 14 March 2020, with identification of references of interest for the topic. The metaanalysis of eligible studies was done using R software package meta, following the PRISMA and MOOSE guidelines. Results: Compared with age-and sex-matched controls, PD patients showed decreased CSF levels of glutamate and taurine and increased CSF levels of tyrosine; decreased serum/plasma levels of aspartate, serine, tryptophan and lysine, and increased serum/plasma proline and homocysteine levels. Conclusion: Despite the limitations of this study due to the important variability of results between different series, our findings suggest the value of CSF or serum/plasma levels of several amino acids in the discrimination of PD patients from healthy subjects, related to the levels of some amino acids. Methods Search strategy A complete literature search was undertaken, without language restrictions, using four databases (PubMed,

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“…There are various reviews of the pharmacology of ionotropic [ 5 , 6 ] and metabotropic glutamate receptors [ 7 , 8 ]. There is also a burgeoning literature on the involvement of glutamate receptors in the pathophysiology and therapeutics of Alzheimer’s dementia [ 9 ], Parkinson’s disease [ 10 ], ischemic stroke [ 11 ], epilepsy [ 12 ], autoimmune diseases of the nervous system [ 13 ], and neuropsychiatric disorders such as schizophrenia [ 14 , 15 , 16 ], depression [ 17 , 18 ], and substance abuse/addiction [ 19 ]. As such, the glutamate receptors present a diverse range of important targets for molecular brain imaging by single photon emission computed tomography (SPECT) and positron emission tomography (PET).…”

Section: Introductionmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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Roles of Glutamate Receptors in Parkinson’s Disease

Cited by 109 publications

References 120 publications

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Cerebrospinal and blood levels of amino acids as potential biomarkers for Parkinson’s disease: review and meta‐analysis

A Review of Molecular Imaging of Glutamate Receptors

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