The alteration of serine transporter activity in a cell line model of amyotrophic lateral sclerosis (ALS)

Lee, Na-Young; Kim, Yunha; Ryu, Hoon; Kang, Young‐Sook

doi:10.1016/j.bbrc.2016.12.178

Cited by 14 publications

(20 citation statements)

References 24 publications

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“…It is important to highlight that the same cycle has been proposed to occur also in the placenta to sustain fetus growth and development (Torres-Zamorano et al, 1998 ; Wu et al, 2015 ). For the sake of thoroughness, it has to be stressed that all the substrates mentioned so far are L-amino acids; however, ASCT2, together with ASCT1, is also responsible for distribution of D-serine in brain whose concentration needs to be kept constant because its alteration is linked to neurological disorder such as ALS (Lee et al, 2017 ) (see section Involvement in Human Pathology and Interaction With Drugs).…”

Section: Transport Propertiesmentioning

confidence: 99%

“…As highlighted in section ASCT2 Gene Expression, ASCT2 is involved in several human cancers thus being an important target for drugs. However, besides cancer, ASCT2 expression/function is altered also in other pathological conditions such as IUGR (IntraUterine Growth Restriction) (Aiko et al, 2014 ), ALS (Amyotrophic Lateral Sclerosis) (Lee et al, 2017 ), and schizophrenia (Maucler et al, 2013 ). Being a plasma membrane transporter, ASCT2 could also be either a first level drug target or a relevant player in drug disposition, similarly to LAT1 which is an acknowledged transporter of several amino acid-like drugs (del Amo et al, 2008 ; Fotiadis et al, 2013 ; Scalise et al, 2018a ; Singh and Ecker, 2018 ).…”

Section: Involvement In Human Pathology and Interaction With Drugsmentioning

confidence: 99%

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The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology

Scalise

Pochini

Console

et al. 2018

Front. Cell Dev. Biol.

199

193

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SLC1A5, known as ASCT2, is a neutral amino acid transporter belonging to the SLC1 family and localized in the plasma membrane of several body districts. ASCT2 is an acronym standing for Alanine, Serine, Cysteine Transporter 2 even if the preferred substrate is the conditionally essential amino acid glutamine, with cysteine being a modulator and not a substrate. The studies around amino acid transport in cells and tissues began in the ‘60s by using radiolabeled compounds and competition assays. After identification of murine and human genes, the function of the coded protein has been studied in cell system and in proteoliposomes revealing that this transporter is a Na+ dependent antiporter of neutral amino acids, some of which are only inwardly transported and others are bi-directionally exchanged. The functional asymmetry merged with the kinetic asymmetry in line with the physiological role of amino acid pool harmonization. An intriguing function has been described for ASCT2 that is exploited as a receptor by a group of retroviruses to infect human cells. Interactions with scaffold proteins and post-translational modifications regulate ASCT2 stability, trafficking and transport activity. Two asparagine residues, namely N163 and N212, are the sites of glycosylation that is responsible for the definitive localization into the plasma membrane. ASCT2 expression increases in highly proliferative cells such as inflammatory and stem cells to fulfill the augmented glutamine demand. Interestingly, for the same reason, the expression of ASCT2 is greatly enhanced in many human cancers. This finding has generated interest in its candidacy as a pharmacological target for new anticancer drugs. The recently solved 3D structure of ASCT2 will aid in the rational design of such therapeutic compounds.

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Section: Transport Propertiesmentioning

confidence: 99%

Section: Involvement In Human Pathology and Interaction With Drugsmentioning

confidence: 99%

The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology

Scalise

Pochini

Console

et al. 2018

Front. Cell Dev. Biol.

199

193

View full text Add to dashboard Cite

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“…Levels of synaptic D-serine and L-serine are regulated predominantly by three transporters, the Na + -independent alanine-serine-cysteine 1 transporter (Asc-1) which is a high affinity neuronal transporter selective for D- and L- amino acids, the Na + -dependent alanine-serine-cysteine-threonine 2 transporter (ASCT2) with higher affinity for L-amino acids than D-amino acids and alanine-serine-cysteine-threonine 1 transporter (ASCT1) which has a high affinity for small neutral L amino acids. Studies on the effects of the G93A SOD1 mutation on the activity of these transporters in a motor neuron cell line, NSC-34, showed that D-serine uptake was significantly impaired by the mutation, where the K M for D-serine was increased but no change occurred in V max (Lee et al, 2017 ). In contrast, L-serine uptake was increased.…”

Section: Introductionmentioning

confidence: 99%

Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS)

Kondori

Paul

Robbins

et al. 2018

Front. Mol. Biosci.

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We have investigated a pathogenic mutation in D-amino acid oxidase (DAO), DAOR199W, associated with familial Amyotrophic Lateral Sclerosis (ALS) that impairs D-serine metabolism and causes protein aggregation, autophagy and cell death in motor neuron cell lines. These features are consistent with the pathogenic processes occurring in ALS but most importantly, we have demonstrated that activation of the formation of ubiquitinated protein inclusions, increased autophagosome production and apoptotic cell death caused by the mutation in cell lines are attenuated by 5,7-dichlorokynurenic acid (DCKA), a selective inhibitor of the glycine/D-serine binding site of the NMDA receptor. D-serine is an essential co-agonist at this glutamate receptor. This data provides insight into potential upstream mechanisms that involve the action of D-serine at the NMDA receptor and might contribute to neurodegeneration. This is highly relevant to sporadic ALS (SALS), familial ALS, as well as ALS models, where elevated levels of D-serine have been reported and hence has broader clinical therapeutic implications. In order to investigate this further, we have generated a transgenic line expressing the pathogenic mutation, in order to determine whether mice expressing DAOR199W develop a motor phenotype and whether crossing the SOD1G93A model of ALS with mice expressing DAOR199W affects disease progression. We found that heterozygous expression of DAOR199W led to a significant loss of spinal cord motor neurons at 14 months, which is similar to that found in homozygous mice expressing DAOG181R. We hypothesize that DAO has potential for development as a therapeutic agent in ALS.

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“…Protection of SR to the age-related oxidative stress is already suggested to represent such an alternative procedure to rescue memory deficits associated with physiological aging (Haxaire et al, 2012 ). In preclinical studies, SR antagonists such as Phenazine Ethosulfate (Phen-Et) and erythro-β-Hydroxy L-aspartate have been used to investigate SR involvement in specific NMDAR-dependent processes (De Miranda et al, 2002 ; Kim et al, 2005 ; Strísovský et al, 2005 ; Stevens et al, 2010 ), that could represent other pharmacological alternatives to prevent the onset of pathological conditions in which SR activity is facilitated such as ALS, AD or brain trauma (Sasabe et al, 2007 ; Madeira et al, 2015 ; Lee et al, 2017 ; Perez et al, 2017 ; Kondori et al, 2018 ), though the specificity of these pharmacological tools have recently been questioned. However, there is no doubt now that increasing our knowledge of SR-dependent regulation of NMDAR activation certainly represents a key route that will help people keeping potent cognitive abilities throughout lifespan.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, weaker NMDAR activation linked to down regulation of SR activity is now viewed as a critical synaptic dysfunction in schizophrenia, addictions, anxiety disorders, and depression (Coyle, 2006 ; Benneyworth and Coyle, 2012 ; Gómez-Galán et al, 2012 ; Coyle and Balu, 2018 ). On the opposite, up regulation of NMDAR activity due to increased production of d -serine by SR is viewed as a central mechanism for neurodegenerative processes underlying the amyotrophic lateral sclerosis (Sasabe et al, 2007 ; Lee et al, 2017 ; Kondori et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Changes in Serine Racemase-Dependent Modulation of NMDA Receptor: Impact on Physiological and Pathological Brain Aging

Billard

2018

Front. Mol. Biosci.

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The N-methyl-D-Aspartate glutamate receptors (NMDARs) are pivotal for the functional and morphological plasticity that are required in neuronal networks for efficient brain activities and notably for cognitive-related abilities. Because NMDARs are heterogeneous in subunit composition and associated with multiple functional regulatory sites, their efficacy is under the tonic influence of numerous allosteric modulations, whose dysfunction generally represents the first step generating pathological states. Among the enzymatic candidates, serine racemase (SR) has recently gathered an increasing interest considering that it tightly regulates the production of d-serine, an amino acid now viewed as the main endogenous co-agonist necessary for NMDAR activation. Nowadays, SR deregulation is associated with a wide range of neurological and psychiatric diseases including schizophrenia, amyotrophic lateral sclerosis, and depression. This review aims at compelling the most recent experimental evidences indicating that changes in SR-related modulation of NMDARs also govern opposite functional dysfunctions in physiological and pathological (Alzheimer's disease) aging that finally results in memory disabilities in both cases. It also highlights SR as a relevant alternative target for new pharmacological strategies aimed at preventing functional alterations and cognitive impairments linked to the aging process.

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The alteration of serine transporter activity in a cell line model of amyotrophic lateral sclerosis (ALS)

Cited by 14 publications

References 24 publications

The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology

The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology

Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS)

Changes in Serine Racemase-Dependent Modulation of NMDA Receptor: Impact on Physiological and Pathological Brain Aging

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