Mutations associated with epileptic encephalopathy modify EAAT2 anion channel function

Kovermann, Peter; Kolobkova, Yulia; Franzen, Arne; Fahlke, Christoph

doi:10.1111/epi.17154

Cited by 12 publications

(8 citation statements)

References 49 publications

(83 reference statements)

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“…Surplus glutamate is eliminated by glial cells through excitatory amino acid transporters (EAAT1, EAAT2) ( 126 ). Notably, reduced expression levels of EAAT1 and EAAT2 have been observed in cases of epilepsy ( 127 , 128 ), while mutations in the SLC1A3 and SLC1A2 genes that encodes EAAT1 and EAAT2, can result in episodic ataxia 6, characterized by symptoms of epilepsy, long lasting ataxia attacks and headaches, and epileptic encephalopathies, respectively ( 129 , 130 ).…”

Section: Introductionmentioning

confidence: 99%

Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

Vicente,

Addo-Osafo,

Vossel

2024

Front. Neurol.

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Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) stand as the prevailing sources of neurodegenerative dementia, impacting over 55 million individuals across the globe. Patients with AD and DLB exhibit a higher prevalence of epileptic activity compared to those with other forms of dementia. Seizures can accompany AD and DLB in early stages, and the associated epileptic activity can contribute to cognitive symptoms and exacerbate cognitive decline. Aberrant neuronal activity in AD and DLB may be caused by several mechanisms that are not yet understood. Hyperexcitability could be a biomarker for early detection of AD or DLB before the onset of dementia. In this review, we compare and contrast mechanisms of network hyperexcitability in AD and DLB. We examine the contributions of genetic risk factors, Ca2+ dysregulation, glutamate, AMPA and NMDA receptors, mTOR, pathological amyloid beta, tau and α-synuclein, altered microglial and astrocytic activity, and impaired inhibitory interneuron function. By gaining a deeper understanding of the molecular mechanisms that cause neuronal hyperexcitability, we might uncover therapeutic approaches to effectively ease symptoms and slow down the advancement of AD and DLB.

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Section: Introductionmentioning

confidence: 99%

Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

Vicente,

Addo-Osafo,

Vossel

2024

Front. Neurol.

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“…L221V, L221P, and S534L reduced ClC-4 currents to the levels measured in untransfected cells ( Figures 2A,B ). WT and mutant ClC-4 were expressed as eGFP fusion proteins, permitting quantification of transporter expression levels by measuring eGFP fluorescence intensities in individual cells and correlating expression levels and current amplitudes ( Schänzler and Fahlke, 2012 ; Ronstedt et al, 2015 ; Tan et al, 2017 ; Kovermann et al, 2022 ). Figure 2C provides plots of steady-state current amplitudes at +175 mV versus whole-cell fluorescence intensities for HEK293T cells expressing WT or mutant cells.…”

Section: Resultsmentioning

confidence: 99%

Functional Characterization of CLCN4 Variants Associated With X-Linked Intellectual Disability and Epilepsy

Guzman

Sierra-Marquez

Bungert-Plümke

et al. 2022

Front. Mol. Neurosci.

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Early/late endosomes, recycling endosomes, and lysosomes together form the endo-lysosomal recycling pathway. This system plays a crucial role in cell differentiation and survival, and dysregulation of the endo-lysosomal system appears to be important in the pathogenesis of neurodevelopmental and neurodegenerative diseases. Each endo-lysosomal compartment fulfils a specific function, which is supported by ion transporters and channels that modify ion concentrations and electrical gradients across endo-lysosomal membranes. CLC-type Cl–/H+ exchangers are a group of endo-lysosomal transporters that are assumed to regulate luminal acidification and chloride concentration in multiple endosomal compartments. Heterodimers of ClC-3 and ClC-4 localize to various internal membranes, from the endoplasmic reticulum and Golgi to recycling endosomes and late endosomes/lysosomes. The importance of ClC-4-mediated ion transport is illustrated by the association of naturally occurring CLCN4 mutations with epileptic encephalopathy, intellectual disability, and behavioral disorders in human patients. However, how these mutations affect the expression, subcellular localization, and function of ClC-4 is insufficiently understood. We here studied 12 CLCN4 variants that were identified in patients with X-linked intellectual disability and epilepsy and were already characterized to some extent in earlier work. We analyzed the consequences of these mutations on ClC-4 ion transport, subcellular trafficking, and heterodimerization with ClC-3 using heterologous expression in mammalian cells, biochemistry, confocal imaging, and whole-cell patch-clamp recordings. The mutations led to a variety of changes in ClC-4 function, ranging from gain/loss of function and impaired heterodimerization with ClC-3 to subtle impairments in transport functions. Our results suggest that even slight functional changes to the endosomal Cl–/H+ exchangers can cause serious neurological symptoms.

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“…It is worth noting that missense mutations in the critical domain of EAAT2 are able to change the direction of glutamate flow, i.e., G82R and L85P in EAAT2 ( 37 ), which suggests that genetic testing should be performed prior to EAAT2-based therapy in patients with epilepsy to avoid more severe excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological induction of AMFR increases functional EAAT2 oligomer levels and reduces epileptic seizures in mice

Sha¹,

Li²,

Zhang³

et al. 2022

JCI Insight

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Mutations associated with epileptic encephalopathy modify EAAT2 anion channel function

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 12 publications

References 49 publications

Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

Functional Characterization of CLCN4 Variants Associated With X-Linked Intellectual Disability and Epilepsy

Pharmacological induction of AMFR increases functional EAAT2 oligomer levels and reduces epileptic seizures in mice

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