Huntington's disease pattern of transcriptional dysregulation in the absence of mutant huntingtin is produced by knockout of neuronal GLT-1

Laprairie, Robert B.; Petr, Geraldine T.; Sun, Yan; Fischer, Kathryn D.; Denovan‐Wright, Eileen M.; Rosenberg, Paul A.

doi:10.1016/j.neuint.2018.04.015

Cited by 17 publications

(9 citation statements)

References 64 publications

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“…Bioenergetic failure in synapses has been suggested as playing an important role in the pathogenesis of chronic neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, and Alzheimer's disease (Nunnari and Suomalainen, 2012;Pathak et al, 2013;Devine and Kittler, 2018). Recently, KO of GLT-1 in neurons was shown to produce age-dependent changes in expression of a panel of genes also altered in expression in Huntington's disease (Laprairie et al, 2019). It will be of substantial interest to determine the long-term neuropathological and synaptic consequences of the mitochondrial abnormalities in the neuronal GLT-1 KO reported here, and possible relevance of this model for understanding human neurodegenerative disorders.…”

Section: Neuronal Glt-1 Expression Is Important For Synaptic Energy Mmentioning

confidence: 99%

Deletion of Neuronal GLT-1 in Mice Reveals Its Role in Synaptic Glutamate Homeostasis and Mitochondrial Function

et al. 2019

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The glutamate transporter GLT-1 is highly expressed in astrocytes but also in neurons, primarily in axon terminals. We generated a conditional neuronal GLT-1 KO using synapsin 1-Cre (synGLT-1 KO) to elucidate the metabolic functions of GLT-1 expressed in neurons, here focusing on the cerebral cortex. Both synaptosomal uptake studies and electron microscopic immunocytochemistry demonstrated knockdown of GLT-1 in the cerebral cortex in the synGLT-1 KO mice. Aspartate content was significantly reduced in cerebral cortical extracts as well as synaptosomes from cerebral cortex of synGLT-1 KO compared with control littermates. 13 C-Labeling of tricarboxylic acid cycle intermediates originating from metabolism of [U-13 C]-glutamate was significantly reduced in synGLT-1 KO synaptosomes. The decreased aspartate content was due to diminished entry of glutamate into the tricarboxylic acid cycle. Pyruvate recycling, a pathway necessary for full glutamate oxidation, was also decreased. ATP production was significantly increased, despite unaltered oxygen consumption, in isolated mitochondria from the synGLT-1 KO. The density of mitochondria in axon terminals and perisynaptic astrocytes was increased in the synGLT-1 KO. Intramitochondrial cristae density of synGLT-1 KO mice was increased, suggesting increased mitochondrial efficiency, perhaps in compensation for reduced access to glutamate. SynGLT-1 KO synaptosomes exhibited an elevated oxygen consumption rate when stimulated with veratridine, despite a lower baseline oxygen consumption rate in the presence of glucose. GLT-1 expressed in neurons appears to be required to provide glutamate to synaptic mitochondria and is linked to neuronal energy metabolism and mitochondrial function.

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Section: Neuronal Glt-1 Expression Is Important For Synaptic Energy Mmentioning

confidence: 99%

Deletion of Neuronal GLT-1 in Mice Reveals Its Role in Synaptic Glutamate Homeostasis and Mitochondrial Function

et al. 2019

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“…Downregulation of GLT-1 has been observed in HD and may be responsible for the impaired glutamate uptake and glutamate toxicity observed in the R6 model of HD (Lievens et al, 2001; Estrada-Sanchez et al, 2009). Similar changes in gene expression patterns associated with transcriptional dysregulation in HD is observed in neuronal GLT-1 KO mice, suggesting neuronal GLT-1 loss in HD may lead to transcriptional dysregulation (Laprairie et al, 2019). Alzheimer’s disease (AD) is a neurodegenerative disorder which causes the gradual accumulation of Aβ and Aβ-associated proteins (Selkoe, 2000).…”

Section: Introductionmentioning

confidence: 81%

Post-translational Regulation of GLT-1 in Neurological Diseases and Its Potential as an Effective Therapeutic Target

Peterson

Binder

2019

Front. Mol. Neurosci.

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Glutamate transporter-1 (GLT-1) is a Na + -dependent transporter that plays a key role in glutamate homeostasis by removing excess glutamate in the central nervous system (CNS). GLT-1 dysregulation occurs in various neurological diseases including Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and epilepsy. Downregulation or dysfunction of GLT-1 has been a common finding across these diseases but how this occurs is still under investigation. This review aims to highlight post-translational regulation of GLT-1 which leads to its downregulation including sumoylation, palmitoylation, nitrosylation, ubiquitination, and subcellular localization. Various therapeutic interventions to restore GLT-1, their proposed mechanism of action and functional effects will be examined as potential treatments to attenuate the neurological symptoms associated with loss or downregulation of GLT-1.

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“…The physiological roles of the neuronal EAAT2 need further studies, but it is already clear that it does have physiological roles [ 9 ]. The phenotypes so far identified from the neuronal EAAT2 knockouts suggested involvement of glutamate homeostasis and mitochondrial function [ 9 , 208 , 209 ], blunted locomotor response to acute AMP administration [ 210 ]; alteration in expression of cannabinoid receptors, preproenkephalin and PDE10A [ 211 ].…”

Section: Scientific Impact Of This Reconstitution Methodsmentioning

confidence: 99%

Reconstitution of GABA, Glycine and Glutamate Transporters

2021

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In contrast to water soluble enzymes which can be purified and studied while in solution, studies of solute carrier (transporter) proteins require both that the protein of interest is situated in a phospholipid membrane and that this membrane forms a closed compartment. An additional challenge to the study of transporter proteins has been that the transport depends on the transmembrane electrochemical gradients. Baruch I. Kanner understood this early on and first developed techniques for studying plasma membrane vesicles. This advanced the field in that the experimenter could control the electrochemical gradients. Kanner, however, did not stop there, but started to solubilize the membranes so that the transporter proteins were taken out of their natural environment. In order to study them, Kanner then had to find a way to reconstitute them (reinsert them into phospholipid membranes). The scope of the present review is both to describe the reconstitution method in full detail as that has never been done, and also to reveal the scientific impact that this method has had. Kanner’s later work is not reviewed here although that also deserves a review because it too has had a huge impact.

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Huntington's disease pattern of transcriptional dysregulation in the absence of mutant huntingtin is produced by knockout of neuronal GLT-1

Cited by 17 publications

References 64 publications

Deletion of Neuronal GLT-1 in Mice Reveals Its Role in Synaptic Glutamate Homeostasis and Mitochondrial Function

Deletion of Neuronal GLT-1 in Mice Reveals Its Role in Synaptic Glutamate Homeostasis and Mitochondrial Function

Post-translational Regulation of GLT-1 in Neurological Diseases and Its Potential as an Effective Therapeutic Target

Reconstitution of GABA, Glycine and Glutamate Transporters

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