RT Journal Article
T1 Kidins220-deficient hydrocephalus mice exhibit altered glial phenotypes and AQP4 differential regulation in the retina and optic nerve, with preserved retinal ganglion cell survival
A1 Fernández Albarral, José
A1 Simón-García, Ana
A1 García Martín, Elena Salobrar
A1 Salazar, Juan J.
A1 López-Menéndez, Celia
A1 Pajuelo, Luis S. M.
A1 Matamoros Felipe, José Antonio
A1 Hoz Montañana, María Rosa De
A1 López Cuenca, Inés
A1 Elvira-Hurtado, Lorena
A1 Sánchez-Puebla Fernández, Lidia
A1 Sánchez-Carralero, Marina P.
A1 Sanz, Marina
A1 Ramírez, José M
A1 Ramírez, Ana I.
AB Hydrocephalus, characterized by ventriculomegaly due to cerebrospinal fluid accumulation in the cerebral ventricles, is a co-morbidity factor in several neurodevelopmental, psychiatric and neurodegenerative diseases. Aquaporin-4 (AQP4) is crucial for brain water homeostasis, with Aqp4 knockout mice showing sporadic ventriculomegaly and increased brain water content. Kinase D interacting substrate of 220 kDa (Kidins220), a transmembrane protein involved in neuronal survival, synaptic activity and neurogenesis, controls AQP4 levels in ependymocytes and brain astrocytes. Indeed, Kidins220 deficiency in mice leads to hydrocephalus by downregulating VPS35, a key component of the retromer complex, and targeting AQP4 to lysosomal degradation. Importantly, the ependymal barrier of idiopathic normal pressure hydrocephalus patients shows a similar downregulation of KIDINS220 and AQP4. In addition, pathogenic variants in the KIDINS220 gene are linked to SINO syndrome, a rare disorder characterized by spastic paraplegia, intellectual disability, nystagmus, and obesity associated with hydrocephalus and ventriculomegaly. Given the retina's structural and functional similarities to the brain, we hypothesized that Kidins220 deficiency would affect retinal water regulation. However, the diminished expression of Kidins220 and VPS35 in the retina of Kidins220-deficient hydrocephalus mice, did not cause edema or downregulate AQP4 in Müller cells. Surprisingly, there was an increase in AQP4 levels within this glial cell population. Conversely, AQP4 expression in the optic nerve astrocytes was reduced, as observed in brain astrocytes, suggesting a distinctive adaptive response to hydrocephalus in Müller glia within the Kidins220-deficient retina. Furthermore, we observed phenotypic modifications in retinal glia in Kidins220-deficient hydrocephalus mice. However, we did not find any signs of neuronal damage in the retina. Future studies using OCT and OCTA in SINO syndrome patients with ventriculomegaly will be essential in elucidating the relationship between KIDINS220 pathogenic variants, retinal alterations, papilledema, and visual function.
PB PubMed
YR 2025
FD 2025-02
LK https://hdl.handle.net/20.500.14352/118138
UL https://hdl.handle.net/20.500.14352/118138
LA eng
NO Fernández-Albarral JA, Simón-García A, Salobrar-García E, Salazar JJ, López-Menéndez C, Pajuelo LSM, Matamoros JA, de Hoz R, López-Cuenca I, Elvira-Hurtado L, Sanchez-Puebla L, Sánchez-Carralero MP, Sanz M, Ramírez JM, Iglesias T, Ramírez AI. Kidins220-deficient hydrocephalus mice exhibit altered glial phenotypes and AQP4 differential regulation in the retina and optic nerve, with preserved retinal ganglion cell survival. Fluids Barriers CNS. 2025 Feb 12;22(1):16. doi: 10.1186/s12987-025-00626-z. PMID: 39939990; PMCID: PMC11823095.
DS Docta Complutense
RD 5 abr 2025