Structure and Functions of Aquaporin-4-Based Orthogonal Arrays of Particles

Wolburg, Hartwig; Wolburg‐Buchholz, Karen; Fallier‐Becker, Petra; Noell, Susan; Mack, Andreas F.

doi:10.1016/b978-0-12-386043-9.00001-3

Cited by 125 publications

(101 citation statements)

References 227 publications

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“…almost completely ensheath the vascular tube, and contain a discrete array of proteins including dystroclycan, dystrophin, and aquaporin 4. The dysroglycan-dystrophin complex is important to link the endfeet cytoskeleton to the BM by binding agrin Wolburg et al 2011). This linkage coordinates aquaporin 4 into orthogonal arrays of particles, which is critical for regulating water homesostasis in the CNS.…”

Section: Basement Membranementioning

confidence: 99%

The Blood–Brain Barrier

Daneman

Prat

2015

Cold Spring Harb Perspect Biol

2,430

1,829

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Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.

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Section: Basement Membranementioning

confidence: 99%

The Blood–Brain Barrier

Daneman

Prat

2015

Cold Spring Harb Perspect Biol

2,430

1,829

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“…Where the astroglial endfeet contact the superficial or perivascular BL (glia limitans superficialis et perivascularis), the glial membrane contains numerous square arrays or intramembranous OAPs (Wolburg et al, 2011). Where the glial cell membrane loses the contact with the BL and turns into deeper areas of the neuropil, the density of OAPs is dramatically reduced.…”

Section: The Astrocytementioning

confidence: 99%

Current concepts of blood-brain barrier development

Liebner¹,

Czupalla²,

Wolburg³

2011

Int. J. Dev. Biol.

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198

149

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Homeostasis of the central nervous system (CNS) microenvironment is essential for its normal function and is maintained by the blood-brain barrier (BBB). The BBB proper is made up of endothelial cells (ECs) interconnected by tight junctions (TJs) that reveal a unique morphology and biochemical composition of the body's vasculature. In this article, we focus on developmental aspects of the BBB and describe morphological as well as molecular special features of the neurovascular unit (NVU) involved in barrier induction. Recently, we and others identified the Wnt/bcatenin pathway as crucial for brain angiogenesis, TJ and BBB formation. Based on these findings we discuss other pathways and molecular interactions for BBB establishment and maintenance. At the morphological level, our concept favors a major role for polarized astrocytes (ACs) therein. Orthogonal arrays of particles (OAPs) that are the morphological correlate of the water channel protein aquaporin-4 (AQP4) are specifically formed in the membrane of the AC endfoot. The polarized AC endfoot and hence OAPs are dependent on agrin and dystroglycan, of which agrin is a developmentally regulated extracellular matrix (ECM) component. Understanding the mechanisms leading to BBB development will be key to the understanding of barrier maintenance that is crucial for, but frequently disturbed, in the diseased adult brain.

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“…Orthogonal arrays of particles (OAPs) containing AQP4 tetramers are an ultrastructural characteristic of membrane specializations on astrocytic foot processes facing sites of rapidly fluxing potassium ions and water (9,10). OAP size is determined by the M1-to-M23 ratio.…”

mentioning

confidence: 99%

“…OAP size is determined by the M1-to-M23 ratio. In Chinese hamster ovary cells, exogenously expressed M1, without M23, does not form arrays but exists as individual tetramers (10). In the absence of M1, M23 tetramers form high-order arrays in the plasma membrane.…”

mentioning

confidence: 99%

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

Hinson¹,

Romero²,

Popescu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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281

274

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The astrocytic aquaporin-4 (AQP4) water channel is the target of pathogenic antibodies in a spectrum of relapsing autoimmune inflammatory central nervous system disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG. Neuromyelitis optica is the most severe of these disorders. The two major AQP4 isoforms, M1 and M23, have identical extracellular residues. This report identifies two novel properties of NMO-IgG as determinants of pathogenicity. First, the binding of NMO-IgG to the ectodomain of astrocytic AQP4 has isoform-specific outcomes. M1 is completely internalized, but M23 resists internalization and is aggregated into larger-order orthogonal arrays of particles that activate complement more effectively than M1 when bound by NMO-IgG. Second, NMO-IgG binding to either isoform impairs water flux directly, independently of antigen down-regulation. We identified, in nondestructive central nervous system lesions of two NMO patients, two previously unappreciated histopathological correlates supporting the clinical relevance of our in vitro findings: (i) reactive astrocytes with persistent foci of surface AQP4 and (ii) vacuolation in adjacent myelin consistent with edema. The multiple molecular outcomes identified as a consequence of NMO-IgG interaction with AQP4 plausibly account for the diverse pathological features of NMO: edema, inflammation, demyelination, and necrosis. Differences in the nature and anatomical distribution of NMO lesions, and in the clinical and imaging manifestations of disease documented in pediatric and adult patients, may be influenced by regional and maturational differences in the ratio of M1 to M23 proteins in astrocytic membranes.T he most abundant water channel in the central nervous system (CNS) is aquaporin-4 (AQP4), which is confined to astrocytes and ependyma; is enriched at glial-pial and glialendothelial interfaces; and surrounds nodes of Ranvier and paranodes, adjacent oligodendroglial loops, and synapses (1). In 2005, we identified AQP4 as the target of pathogenic autoantibodies in a spectrum of inflammatory CNS disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG (2, 3). These disorders are now recognized collectively as IgG-mediated autoimmune astrocytopathies. Before discovery of this antibody, NMO spectrum disorders were misclassified as multiple sclerosis variants. NMOIgG is centrally involved in the pathogenesis of NMO spectrum disorders. Its detection predicts frequent relapses that cause cumulative neurological impairment. Lesions characteristically affect the spinal cord and optic nerve, but do not spare the brain. Independent laboratories have demonstrated that NMO-IgG binding initiates AQP4 down-regulation with accompanying endocytosis of its physically associated glutamate transporter, EAAT2, complement activation, impairment of blood-brain barrier integrity, inflammation, and astrocyte injury (4-8). Demyelination is a proposed consequence of both pa...

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Structure and Functions of Aquaporin-4-Based Orthogonal Arrays of Particles

Cited by 125 publications

References 227 publications

The Blood–Brain Barrier

The Blood–Brain Barrier

Current concepts of blood-brain barrier development

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

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