Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction

Hoegg-Beiler, Maja B.; Sirisi, Sònia; Orozco, Ian J.; Ferrer, Isidre; Hohensee, Svea; Auberson, Muriel; Gödde, Kathrin; Vilches, Clara; Heredia, Miguel López de; Nunes, Virginia; Estévez, Raúl; Jentsch, Thomas J.

doi:10.1038/ncomms4475

Cited by 95 publications

(245 citation statements)

References 51 publications

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“…In line with the in vitro data, we found that Glialcam disruption in mice affected the abundance and localization of both ClC-2 and Mlc1 in glial cells (Hoegg-Beiler et al 2014). Unexpectedly, also Mlc1 disruption changed both GlialCAM and ClC-2 expression (Hoegg-Beiler et al 2014;Dubey et al 2015).…”

Section: Clc-2: a Widely Expressed CLsupporting

confidence: 72%

“…Consistent with the in vitro data, deletion of GlialCAM (or of Mlc1) reduced ClC-2 currents and introduced inward rectification in oligodendrocytes but, unexpectedly, not in cerebellar Bergmann glia that prominently co-express all three proteins (Hoegg-Beiler et al 2014). The pathology resulting from GlialCAM and Mlc1 disruption cannot be explained only by reduced ClC-2 function because mice lacking both ClC-2 and GlialCAM show more severe leukodystrophy than Clcn2 −/− mice (Hoegg-Beiler et al 2014). ClC-2, GlialCAM and MLC1 are co-expressed at connections between oligodendrocytes and astrocytes and at astrocytic endfeet that contact blood vessels (Blanz et al 2007;Jeworutzki et al 2012;Hoegg-Beiler et al 2014).…”

Section: Clc-2: a Widely Expressed CLsupporting

confidence: 69%

Section: Clc-2: a Widely Expressed CLmentioning

confidence: 99%

“…Unexpectedly, also Mlc1 disruption changed both GlialCAM and ClC-2 expression (Hoegg-Beiler et al 2014;Dubey et al 2015). Consistent with the in vitro data, deletion of GlialCAM (or of Mlc1) reduced ClC-2 currents and introduced inward rectification in oligodendrocytes but, unexpectedly, not in cerebellar Bergmann glia that prominently co-express all three proteins (Hoegg-Beiler et al 2014). The pathology resulting from GlialCAM and Mlc1 disruption cannot be explained only by reduced ClC-2 function because mice lacking both ClC-2 and GlialCAM show more severe leukodystrophy than Clcn2 −/− mice (Hoegg-Beiler et al 2014).…”

Section: Clc-2: a Widely Expressed CLmentioning

confidence: 99%

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Discovery of CLC transport proteins: cloning, structure, function and pathophysiology

Jentsch

2015

J Physiol

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After providing a personal description of the convoluted path leading 25 years ago to the molecular identification of the Torpedo Cl − channel ClC-0 and the discovery of the CLC gene family, I succinctly describe the general structural and functional features of these ion transporters before giving a short overview of mammalian CLCs. These can be categorized into plasma membrane Cl − channels and vesicular Cl − /H + -exchangers. They are involved in the regulation of membrane excitability, transepithelial transport, extracellular ion homeostasis, endocytosis and lysosomal function. Diseases caused by CLC dysfunction include myotonia, neurodegeneration, deafness, blindness, leukodystrophy, male infertility, renal salt loss, kidney stones and osteopetrosis, revealing a surprisingly broad spectrum of biological roles for chloride transport that was unsuspected when I set out to clone the first voltage-gated chloride channel.

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Section: Clc-2: a Widely Expressed CLsupporting

confidence: 72%

Section: Clc-2: a Widely Expressed CLsupporting

confidence: 69%

Section: Clc-2: a Widely Expressed CLmentioning

confidence: 99%

Section: Clc-2: a Widely Expressed CLmentioning

confidence: 99%

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Discovery of CLC transport proteins: cloning, structure, function and pathophysiology

Jentsch

2015

J Physiol

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“…MLC1 is a membrane protein almost exclusively expressed in brain astrocytes 5. GlialCAM is a chaperone of MLC1, ensuring its localization in the membrane of astrocyte endfeet 4, 6, 7. Patients show very high water content in the brain white matter.…”

mentioning

confidence: 99%

Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

Dubey

Brouwers

Hamilton

et al. 2018

Annals of Neurology

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ObjectiveLoss of function of the astrocyte‐specific protein MLC1 leads to the childhood‐onset leukodystrophy “megalencephalic leukoencephalopathy with subcortical cysts” (MLC). Studies on isolated cells show a role for MLC1 in astrocyte volume regulation and suggest that disturbed brain ion and water homeostasis is central to the disease. Excitability of neuronal networks is particularly sensitive to ion and water homeostasis. In line with this, reports of seizures and epilepsy in MLC patients exist. However, systematic assessment and mechanistic understanding of seizures in MLC are lacking.MethodsWe analyzed an MLC patient inventory to study occurrence of seizures in MLC. We used two distinct genetic mouse models of MLC to further study epileptiform activity and seizure threshold through wireless extracellular field potential recordings. Whole‐cell patch‐clamp recordings and K+‐sensitive electrode recordings in mouse brain slices were used to explore the underlying mechanisms of epilepsy in MLC.ResultsAn early onset of seizures is common in MLC. Similarly, in MLC mice, we uncovered spontaneous epileptiform brain activity and a lowered threshold for induced seizures. At the cellular level, we found that although passive and active properties of individual pyramidal neurons are unchanged, extracellular K+ dynamics and neuronal network activity are abnormal in MLC mice.InterpretationDisturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures. These findings suggest a role for defective astrocyte volume regulation in epilepsy. Ann Neurol 2018;83:636–649

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Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

Bugiani

Dubey

Breur

et al. 2017

Ann Clin Transl Neurol

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ObjectiveMegalencephalic leukoencephalopathy with cysts (MLC) is a genetic infantile‐onset disease characterized by macrocephaly and white matter edema due to loss of MLC1 function. Recessive mutations in either MLC1 or GLIALCAM cause the disease. MLC1 is involved in astrocytic volume regulation; GlialCAM ensures the correct membrane localization of MLC1. Their exact role in brain ion‐water homeostasis is only partly defined. We characterized Glialcam‐null mice for further studies.MethodsWe investigated the consequences of loss of GlialCAM in Glialcam‐null mice and compared GlialCAM developmental expression in mice and men.Results Glialcam‐null mice had early‐onset megalencephaly and increased brain water content. From 3 weeks, astrocytes were abnormal with swollen processes abutting blood vessels. Concomitantly, progressive white matter vacuolization developed due to intramyelinic edema. Glialcam‐null astrocytes showed abolished expression of MLC1, reduced expression of the chloride channel ClC‐2 and increased expression and redistribution of the water channel aquaporin4. Expression of other MLC1‐interacting proteins and the volume regulated anion channel LRRC8A was unchanged. In mice, GlialCAM expression increased until 3 weeks and then stabilized. In humans, GlialCAM expression was highest in the first 3 years to then decrease and stabilize from approximately 5 years.Interpretation Glialcam‐null mice replicate the early stages of the human disease with early‐onset intramyelinic edema. The earliest change is astrocytic swelling, further substantiating that a defect in astrocytic volume regulation is the primary cellular defect in MLC. GlialCAM expression affects expression of MLC1, ClC‐2 and aquaporin4, indicating that abnormal interplay between these proteins is a disease mechanism in megalencephalic leukoencephalopathy with cysts.

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Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction

Cited by 95 publications

References 51 publications

Discovery of CLC transport proteins: cloning, structure, function and pathophysiology

Discovery of CLC transport proteins: cloning, structure, function and pathophysiology

Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

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