Nadia Skauli

• Katoozi, Shirin; Shreyas, Rao; Skauli, Nadia; Froehner, Stanley C.; Ottersen, Ole Petter; Adams, Marv & Amiry-Moghaddam, Mahmood (2020). Functional specialization of retinal Müller cell endfeet depends on an interplay between two syntrophin isoforms. Molecular Brain.  ISSN 1756-6606.  13 . doi: 10.1186/s13041-020-00581-w Full text in Research Archive. Show summary

  Retinal Müller cells are highly polarized macroglial cells with accumulation of the aquaporin-4 (AQP4) water channel and the inwardly rectifying potassium channel Kir4.1 at specialized endfoot membrane domains abutting microvessels and corpus vitreum. Proper water and potassium homeostasis in retina depends on these membrane specializations. Here we show that targeted deletion of β1-syntrophin leads to a partial loss of AQP4 from perivascular Müller cell endfeet and that a concomitant deletion of both α1- and β1-syntrophin causes a near complete loss of AQP4 from both perivascular and subvitreal endfoot membranes. α1-syntrophin is normally very weakly expressed in Müller cell endfeet but β1-syntrophin knockout mice display an increased amount of α1-syntrophin at these sites. We suggest that upregulation of perivascular α1-syntrophin restricts the effect of β1-syntrophin deletion. The present findings indicate that β1-syntrophin plays an important role in maintaining the functional polarity of Müller cells and that α1-syntrophin can partially substitute for β1-syntrophin in AQP4 anchoring. Functional polarization of Müller cells thus depends on an interplay between two syntrophin isoforms.

• Katoozi, Shirin; Skauli, Nadia; Rahmani, Soulmaz; Deshpande, Tushar; Ezan, Pascal; Palazzo, Claudia; Steinhäuser, Christian; Frigeri, Antonio; Cohen-Salmon, Martine; Ottersen, Ole Petter & Amiry-Moghaddam, Mahmood (2020). Uncoupling of the Astrocyte Syncytium Differentially Affects AQP4 Isoforms. Cells.  ISSN 2073-4409. . doi: 10.3390/cells9020382 Full text in Research Archive. Show summary

  The water channel protein aquaporin-4 (AQP4) and the gap junction forming proteins connexin-43 (Cx43) and connexin-30 (Cx30) are astrocytic proteins critically involved in brain water and ion homeostasis. While AQP4 is mainly involved in water flux across the astrocytic endfeet membranes, astrocytic gap junctions provide syncytial coupling allowing intercellular exchange of water, ions, and other molecules. We have previously shown that mice with targeted deletion of Aqp4 display enhanced gap junctional coupling between astrocytes. Here, we investigate whether uncoupling of the astrocytic syncytium by deletion of the astrocytic connexins Cx43 and Cx30 affects AQP4 membrane localization and expression. By using quantitative immunogold cytochemistry, we show that deletion of astrocytic connexins leads to a substantial reduction of perivascular AQP4, concomitant with a down-regulation of total AQP4 protein and mRNA. Isoform expression analysis shows that while the level of the predominant AQP4 M23 isoform is reduced in Cx43/Cx30 double deficient hippocampal astrocytes, the levels of M1, and the alternative translation AQP4ex isoform protein levels are increased. These findings reveal a complex interdependence between AQP4 and connexins, which are both significantly involved in homeostatic functions and astrogliopathologies.

• Prydz, Agnete; Stahl, Katja; Rahmani, Soulmaz; Skauli, Nadia; Skare, Øivind; Ottersen, Ole Petter & Amiry-Moghaddam, Mahmood (2020). Pro-inflammatory role of AQP4 in mice subjected to intrastriatal injections of the Parkinsonogenic toxin MPP. Cells.  ISSN 2073-4409.  9:2418(11) . doi: 10.3390/cells9112418 Full text in Research Archive. Show summary

  Aquaporin-4 (AQP4) is critically involved in brain water and volume homeostasis and has been implicated in a wide range of pathological conditions. Notably, evidence has been accrued to suggest that AQP4 plays a proinflammatory role by promoting release of astrocytic cytokines that activate microglia and other astrocytes. Neuroinflammation is a hallmark of Parkinson's disease (PD), and we have previously shown that astrocytes in substantia nigra (SN) are enriched in AQP4 relative to cortical astrocytes, and that their complement of AQP4 is further increased following treatment with the parkinsonogenic toxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Here, we investigated the effect of Aqp4 deletion on microglial activation in mice subjected to unilateral intrastriatal injection of 1-methyl-4-phenylpyridinium (MPP+, the toxic metabolite of MPTP). Our results show that MPP+ injections lead to a pronounced increase in the expression level of microglial activating genes in the ventral mesencephalon of wild type (WT) mice, but not Aqp4-/- mice. We also show, in WT mice, that MPP+ injections cause an upregulation of nigral AQP4 and swelling of astrocytic endfeet. These findings are consistent with the idea that AQP4 plays a pro-inflammatory role in Parkinson's disease, secondary to the dysregulation of astrocytic volume homeostasis.

• Rao, Shreyas Balachandra; Katoozi, Shirin; Skauli, Nadia; Froehner, Stanley C.; Ottersen, Ole Petter; Adams, Marvin E. & Amiry-Moghaddam, Mahmood (2019). Targeted deletion of β1-syntrophin causes a loss of Kir 4.1 from Müller cell endfeet in mouse retina. Glia.  ISSN 0894-1491.  67(6), s 1138- 1149 . doi: 10.1002/glia.23600 Full text in Research Archive.
• Stahl, Katja; Rahmani, Soulmaz; Prydz, Agnete; Skauli, Nadia; MacAulay, Nanna; Mylonakou, Maria-Niki; Torp, Reidun; Skare, Øivind; Berg, Torill; Leergaard, Trygve Brauns; Paulsen, Ragnhild Elisabeth; Ottersen, Ole Petter & Amiry-Moghaddam, Mahmood (2018). Targeted deletion of the aquaglyceroporin AQP9 is protective in a mouse model of Parkinson's disease. PLOS ONE.  ISSN 1932-6203.  13(3) . doi: 10.1371/journal.pone.0194896 Full text in Research Archive. Show summary

  More than 90% of the cases of Parkinson’s disease have unknown etiology. Gradual loss of dopaminergic neurons of substantia nigra is the main cause of morbidity in this disease. External factors such as environmental toxins are believed to play a role in the cell loss, although the cause of the selective vulnerability of dopaminergic neurons remains unknown. We have previously shown that aquaglyceroporin AQP9 is expressed in dopaminergic neurons and astrocytes of rodent brain. AQP9 is permeable to a broad spectrum of substrates including purines, pyrimidines, and lactate, in addition to water and glycerol. Here we test our hypothesis that AQP9 serves as an influx route for exogenous toxins and, hence, may contribute to the selective vulnerability of nigral dopaminergic (tyrosine hydroxylase-positive) neurons. Using Xenopus oocytes injected with Aqp9 cRNA, we show that AQP9 is permeable to the parkinsonogenic toxin 1-methyl-4-phenylpyridinium (MPP+). Stable expression of AQP9 in HEK cells increases their vulnerability to MPP+ and to arsenite—another parkinsonogenic toxin. Conversely, targeted deletion of Aqp9 in mice protects nigral dopaminergic neurons against MPP+ toxicity. A protective effect of Aqp9 deletion was demonstrated in organotypic slice cultures of mouse midbrain exposed to MPP+ in vitro and in mice subjected to intrastriatal injections of MPP+ in vivo. Seven days after intrastriatal MPP+ injections, the population of tyrosine hydroxylase-positive cells in substantia nigra is reduced by 48% in Aqp9 knockout mice compared with 67% in WT littermates. Our results show that AQP9 –selectively expressed in catecholaminergic neurons—is permeable to MPP+ and suggest that this aquaglyceroporin contributes to the selective vulnerability of nigral dopaminergic neurons by providing an entry route for parkinsonogenic toxins. To our knowledge this is the first evidence implicating a toxin permeable membrane channel in the pathophysiology of Parkinson’s disease.

• Katoozi, Shirin; Skauli, Nadia; Rahmani, Soulmaz; Camassa, Laura Maria Azzurra; Boldt, Henning Bunsow; Ottersen, Ole Petter & Amiry-Moghaddam, Mahmood (2017). Targeted deletion of Aqp4 promotes the formation of astrocytic gap junctions. Brain Structure and Function.  ISSN 1863-2653.  s 1- 14 . doi: 10.1007/s00429-017-1448-5
• Skauli, Nadia; Wallace, Sean Ciaran; Chiang, Samuel C.C.; Barøy, Tuva; Holmgren, Asbjørn; Stray-Pedersen, Asbjørg; Bryceson, Yenan T.; Strømme, Petter; Frengen, Eirik & Misceo, Doriana (2016). Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype. Genes.  ISSN 2073-4425.  7(12) . doi: 10.3390/genes7120108 Show summary

  Biallelic PIGT variants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygous PIGT missense variant c.1079G>T (p.Gly360Val) in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies. PIGT encodes a crucial subunit of the glycosylphosphatidylinositol (GPI) transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novel PIGT variant.

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