Excitotoxic neurodegeneration is associated with a focal decrease in metabotropic glutamate receptor type 5 availability: an in vivo PET imaging study

Crabbé, Melissa; Dirkx, Nina; Casteels, Cindy; Laere, Koen Van

doi:10.1038/s41598-019-49356-x

Cited by 11 publications

(3 citation statements)

References 48 publications

(51 reference statements)

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“…PM neuronal cells demonstrate reduced expression of glutamate (Glu) transporters and the mGluR5 receptor, both of which are key mediators of calcium signaling (Cao et al, 2013;Pretto et al, 2014). Attenuated Glu signaling due to decreased mGluR5 availability is associated with increased excitotoxicity in many neurodegenerative disorders (Lewerenz and Maher, 2015;Crabbé et al, 2019) and may contribute to calcium dysfunction as well as downstream cdk5-ATM dysregulation in FXTAS.…”

Section: Cell Adhesion Extracellular Matrix and Actin Cytoskeletonmentioning

confidence: 99%

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

Holm

Herren

Taylor

et al. 2021

Front. Mol. Biosci.

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Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation CGG-repeat expansions (55–200 repeats) in the 5′ non-coding portion of the fragile X mental retardation 1 (FMR1) gene. Core features of FXTAS include progressive tremor/ataxia, cognitive decline, variable brain volume loss, and white matter disease. The principal histopathological feature of FXTAS is the presence of central nervous system (CNS) and non-CNS intranuclear inclusions.Objective: To further elucidate the molecular underpinnings of FXTAS through the proteomic characterization of human FXTAS cortexes.Results: Proteomic analysis of FXTAS brain cortical tissue (n = 8) identified minor differences in protein abundance compared to control brains (n = 6). Significant differences in FXTAS relative to control brain predominantly involved decreased abundance of proteins, with the greatest decreases observed for tenascin-C (TNC), cluster of differentiation 38 (CD38), and phosphoserine aminotransferase 1 (PSAT1); proteins typically increased in other neurodegenerative diseases. Proteins with the greatest increased abundance include potentially novel neurodegeneration-related proteins and small ubiquitin-like modifier 1/2 (SUMO1/2). The FMRpolyG peptide, proposed in models of FXTAS pathogenesis but only identified in trace amounts in the earlier study of FXTAS inclusions, was not identified in any of the FXTAS or control brains in the current study.Discussion: The observed proteomic shifts, while generally relatively modest, do show a bias toward decreased protein abundance with FXTAS. Such shifts in protein abundance also suggest altered RNA binding as well as loss of cell–cell adhesion/structural integrity. Unlike other neurodegenerative diseases, the proteome of end-stage FXTAS does not suggest a strong inflammation-mediated degenerative response.

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Section: Cell Adhesion Extracellular Matrix and Actin Cytoskeletonmentioning

confidence: 99%

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

Holm

Herren

Taylor

et al. 2021

Front. Mol. Biosci.

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“…GA has potent neurotoxic effects, and this could represent a challenge for either experimental or clinical use. Elevated amounts of GA lead to neuronal death in a process described as excitotoxicity [27][28][29] . GA transporters are a potent GA uptake system, acting as a neuronal compensatory response for excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Glutamic acid promotes hair growth in mice

Jara

Berti

Mendes

et al. 2021

Sci Rep

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Glutamic acid is the main excitatory neurotransmitter acting both in the brain and in peripheral tissues. Abnormal distribution of glutamic acid receptors occurs in skin hyperproliferative conditions such as psoriasis and skin regeneration; however, the biological function of glutamic acid in the skin remains unclear. Using ex vivo, in vivo and in silico approaches, we showed that exogenous glutamic acid promotes hair growth and keratinocyte proliferation. Topical application of glutamic acid decreased the expression of genes related to apoptosis in the skin, whereas glutamic acid increased cell viability and proliferation in human keratinocyte cultures. In addition, we identified the keratinocyte glutamic acid excitotoxic concentration, providing evidence for the existence of a novel skin signalling pathway mediated by a neurotransmitter that controls keratinocyte and hair follicle proliferation. Thus, glutamic acid emerges as a component of the peripheral nervous system that acts to control cell growth in the skin. These results raise the perspective of the pharmacological and nutritional use of glutamic acid to treat skin diseases.

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“…While the relevance of hippocampal mGluR5 loss in AD needs to be fully elucidated, taken together with findings of decreased hippocampal ( 11 C)UCB-J binding in AD [194], the loss of mGluR5 could reflect nonspecific synaptic loss. Conversely, the specific synaptotoxicity of amyloid-β at mGluR sites could influence the spatial distribution of mGlu5R loss [287] and could be related to excitotoxin-induced neurodegeneration [288]. Reductions of ( 11 C)ABP688 PET uptake have also been reported in patients with the behavior variant FTD (bvFTD) [289].…”

Section: Neurotransmitter Dysregulationmentioning

confidence: 99%

Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

Wilson

Politis

Rabiner

et al. 2020

Cells

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There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers.

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Excitotoxic neurodegeneration is associated with a focal decrease in metabotropic glutamate receptor type 5 availability: an in vivo PET imaging study

Cited by 11 publications

References 48 publications

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

Glutamic acid promotes hair growth in mice

Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

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