Altered lactate metabolism in Huntington's disease is dependent on <scp>GLUT</scp>3 expression

Solís-Maldonado, Macarena; Miró, María Paz; Acuña, Aníbal I.; Covarrubias‐Pinto, Adriana; Loaiza, Anitsi; Mayorga, Gonzalo; Beltrán, Felipe A.; Cepeda, Carlos; Levine, Michael S.; Concha, Ilona I.; Bátiz, Luis Federico; Carrasco, Mónica A.; Castro, Maite A.

doi:10.1111/cns.12837

Cited by 17 publications

(17 citation statements)

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“…These evidences implied that abnormal MCTs expression in the hippocampus together with other parts of the limbic system may simultaneously play roles in cognitive deficits. However, a mice model of Huntington's disease has found an increase in lactate up-take and the catalytic efficiency of hippocampal membrane MCT2, while no significant increases have been found in protein or mRNA levels (Solís-Maldonado et al, 2018).…”

Section: Discussionmentioning

confidence: 97%

“…MCTs that take part in ANLS are indispensable for normal CNS energy support, especially for CNS glutamatergic synaptic plasticity, which is crucial for learning and memory; and disturbances in cerebral MCT expression lead to ANLS and cognitive dysfunction (Halestrap and Price, 1999;Belanger et al, 2011;Suzuki et al, 2011;Khatri and Man, 2013). The expression of MCT1 and MCT4 is mainly localized in astrocytes (Pellerin et al, 2005;Solís-Maldonado et al, 2018), and the expression of MCT2 occurs mainly in neurons (Vannucci and Simpson, 2003). FIGURE 3 | Spatial working memory performance of mice in RAM tests following 6 months of ketamine administration with different doses of ketamine 30 mg/kg and 60 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

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Redistribution of Monocarboxylate 1 and 4 in Hippocampus and Spatial Memory Impairment Induced by Long-term Ketamine Administration

Ding

Tan

et al. 2020

Front. Behav. Neurosci.

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The monocarboxylate transporters (MCTs) MCT1, MCT2, and MCT4 are essential components of the astrocyte-neuron lactate shuttle (ANLS), which is a fundamental element of brain energetics. Decreased expression of MCTs can induce cognitive dysfunction of the brain. In the present study, we established a mouse model of long-term ketamine administration by subjecting mice to a 6-month course of a daily intraperitoneal injection of ketamine. These mice demonstrated learning and memory deficits and a significant decline in MCT1 and MCT4 proteins in the hippocampal membrane fraction, while cytoplasmic MCT1 and MCT4 protein levels were significantly increased. In contrast, the levels of global MCT2 protein were significantly increased. Analysis of mRNA levels found no changes in MCT1/4 transcripts, although the expression of MCT2 mRNA was significantly increased. We suggest that redistribution of hippocampal MCT1 and MCT4, but not MCT2 up-regulation, may be related to learning and memory deficits induced by long-term ketamine administration.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Redistribution of Monocarboxylate 1 and 4 in Hippocampus and Spatial Memory Impairment Induced by Long-term Ketamine Administration

Ding

Tan

et al. 2020

Front. Behav. Neurosci.

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“…HD is also characterized by a strong redox imbalance (Browne, Ferrante, & Beal, 1999;Hersch et al, 2006;Mazziotta et al, 1987;Santamaria et al, 2001;Sorolla et al, 2008) as well as defects in brain energy metabolism preceding the disease onset (Gines et al, 2003;Kuwert et al, 1993;Leenders, Frackowiak, Quinn, & Marsden, 1986;Mazziotta et al, 1987;Powers et al, 2007). In our previous studies, we observed altered ascorbic acid uptake and energy metabolism in presymptomatic and symptomatic cellular and animal models of HD (Acuña et al, 2013;Covarrubias-Pinto et al, 2015;Solis-Maldonado et al, 2018).…”

Section: Introductionmentioning

confidence: 87%

Impaired intracellular trafficking of sodium‐dependent vitamin C transporter 2 contributes to the redox imbalance in Huntington’s disease

Covarrubias‐Pinto

Parra

Mayorga-Weber

et al. 2020

J of Neuroscience Research

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Huntington's disease (HD) is a neurodegenerative disorder caused by a glutamine expansion at the first exon of the huntingtin gene. Huntingtin protein (Htt) is ubiquitously expressed and it is localized in several organelles, including endosomes. HD is associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. It is transported into neurons via the sodium‐dependent vitamin C transporter 2 (SVCT2). During synaptic activity, ascorbic acid is released from glial reservoirs to the extracellular space, inducing an increase in SVCT2 localization at the plasma membrane. Here, we studied SVCT2 trafficking and localization in HD. SVCT2 is decreased at synaptic terminals in YAC128 male mice. Using cellular models for HD (STHdhQ7 and STHdhQ111 cells), we determined that SVCT2 trafficking through secretory and endosomal pathways is altered in resting conditions. We observed Golgi fragmentation and SVCT2/Htt‐associated protein‐1 mis‐colocalization. Additionally, we observed altered ascorbic acid‐induced calcium signaling that explains the reduced SVCT2 translocation to the plasma membrane in the presence of extracellular ascorbic acid (active conditions) described in our previous results. Therefore, SVCT2 trafficking to the plasma membrane is altered in resting and active conditions in HD, explaining the redox imbalance observed during early stages of the disease.

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“…Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain diseases. Its involvement in neurodegenerative diseases for instance Huntington’s disease (Vittori et al, 2014; Morea et al, 2017; Solís-Maldonado et al, 2018), Alzheimer’s disease (Liu et al, 2008; An et al, 2018; Gu et al, 2018; Griffith et al, 2019) and glioblastoma (Cosset et al, 2017) is increasingly apparent. In addition, SLC2A3 was identified as a potential risk gene or to display aberrant expression in several psychiatric disorders such as schizophrenia (Kuzman et al, 2009; De Silva, 2011; Sullivan et al, 2018), dyslexia (Roeske et al, 2011; Skeide et al, 2015), affective disorders (Yang et al, 2009), autism (Zhao et al, 2010; O’Roak et al, 2012; Dai et al, 2017) and attention-deficit/hyperactivity disorder (ADHD; Lesch et al, 2011; Merker et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Transcript Analysis of Zebrafish GLUT3 Genes, slc2a3a and slc2a3b, Define Overlapping as Well as Distinct Expression Domains in the Zebrafish (Danio rerio) Central Nervous System

Lechermeier

Zimmer

Lüffe

et al. 2019

Front. Mol. Neurosci.

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The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo . GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish ( Danio rerio ) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b . Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a . Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders.

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Altered lactate metabolism in Huntington's disease is dependent on GLUT3 expression

Cited by 17 publications

References 53 publications

Redistribution of Monocarboxylate 1 and 4 in Hippocampus and Spatial Memory Impairment Induced by Long-term Ketamine Administration

Redistribution of Monocarboxylate 1 and 4 in Hippocampus and Spatial Memory Impairment Induced by Long-term Ketamine Administration

Impaired intracellular trafficking of sodium‐dependent vitamin C transporter 2 contributes to the redox imbalance in Huntington’s disease

Transcript Analysis of Zebrafish GLUT3 Genes, slc2a3a and slc2a3b, Define Overlapping as Well as Distinct Expression Domains in the Zebrafish (Danio rerio) Central Nervous System

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