Genetic Dys-regulation of Astrocytic Glutamate Transporter EAAT2 and its Implications in Neurological Disorders and Manganese Toxicity

Abstract

Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 [glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) in rodents, respectively], are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms (SNPs) and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via NF-κB and CREB at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 (YY1) plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics, and translational regulation of EAAT2.

The Potential Role of Astrocytes in Parkinson’s Disease (PD)

“…PD results primarily from the progressive, selective, and irreversible massive loss of dopaminergic (DA) neurons in the SNpc [4,12,32,33], and the formation of Lewy bodies [3,32,33]. It is most common in older aged individuals, and characterized by a decrease or loss of movement, rigidity, rest tremor, and bradykinesia of impaired motor symptoms [32,34,35]. Pathologically, these symptoms are associated with the loss of dopaminergic neurons in the SNpc [5,32,35].…”

“…It is most common in older aged individuals, and characterized by a decrease or loss of movement, rigidity, rest tremor, and bradykinesia of impaired motor symptoms [32,34,35]. Pathologically, these symptoms are associated with the loss of dopaminergic neurons in the SNpc [5,32,35]. Therefore, the protection of substantia nigral dopamine neurons from progressive degenerative death, and cell replacement of novel dopamine neurons, are hopeful strategies against PD in humans [5,33].…”

“…Recent studies have shown that the sub-thalamic nucleus receives direct excitatory projections from the primary motor cortex [36], and dopaminergic projections from the SNpc [36,37] and striatum [38]. Therefore, the degeneration of dopaminergic neurons in the substantia nigra (SN) influences the direct, and indirect, pathway in the basal ganglia microcircuits [35].…”

Astrocytes and Microglia as Non-cell Autonomous Players in the Pathogenesis of ALS

“…Excitatory amino acid transporter-2 (EAAT2) is known as a typical glial glutamate transporter that uptakes neurotransmitters glutamate and aspartate from the synaptic cleft [31]. It is believed that EAAT2 uptakes more than 90% of glutamate into glia.…”

Excitotoxicity: An Organized Crime at The Cellular Level

“…This highlights the necessary presence of neurons and glia cells for the expression of these transporters [86]. Epigenetic factors are also involved in EAAT2 expression, including CpG promoter methylation, which is lower in astrocytes in isolated cultures as well [87].…”