Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation

• DOI: 10.1038/s41380-021-01127-9
• Publication Date: 2021-05-17T10:04:53Z
• Authors: Ana del Puerto; Julia Pose-Utrilla; Ana Simón-García; Celia López-Menéndez; Antonio J. Jiménez; Eva Porlan; Luis S. M. Pajuelo; Guillermo Cano-Ga...; Beatriz Martí-Prado; Álvaro Sebastián-...; Marina P. Sánchez...; Fabrizia Cesca; Giampietro Schiavo; Isidro Ferrer; Isabel Fariñas; Miguel R. Campanero; Teresa Iglesias
• Keywords: Retromer; Ependymal Cell; Ventriculomegaly

Abstract Several psychiatric, neurologic and neurodegenerative disorders present increased brain ventricles volume, being hydrocephalus the disease with major manifestation of ventriculomegaly caused by accumulation high amounts cerebrospinal fluid (CSF). The molecules pathomechanisms underlying cerebral ventricular enlargement are widely unknown. Kinase D interacting substrate 220 kDa ( KIDINS220) gene has been recently associated schizophrenia a novel syndrome characterized spastic paraplegia, intellectual disability, nystagmus obesity (SINO syndrome), diseases frequently occurring ventriculomegaly. Here we show that Kidins220, transmembrane protein effector various key neuronal signalling pathways, is critical regulator CSF homeostasis. We observe both KIDINS220 water channel aquaporin-4 (AQP4) markedly downregulated at ependymal lining idiopathic normal pressure (iNPH) patients. also find Kidins220 deficient mice develop accompanied dyshomeostasis loss AQP4 in layer astrocytes. known cargo SNX27-retromer, complex redirects endocytosed plasma membrane proteins (cargos) back to cell surface, thus avoiding their targeting lysosomes for degradation. Mechanistically, SNX27-retromer deficiency promotes striking unexpected downregulation results lysosomal Accordingly, SNX27 silencing decreases levels wild-type astrocytes whereas overexpression restores content Together our data suggest KIDINS220-SNX27-retromer-AQP4 pathway involved human open therapeutic perspectives.