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

Abstract

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

Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis

“…To directly examine NSCs at the ventricular surface of Kidins220 mutants, we used whole mount en face staining of NSCs. As previously described for Kidins220 f/f [23], Kidins220 GfapΔ/Δ ventricular wall linings were apparently normal, showing multiciliated ependymal cells (Fig. 1G).…”

“…The copyright holder for this this version posted January 10, 2023. ; https://doi.org/10.1101/2023.01.10.523252 doi: bioRxiv preprint primary cilium (γ-tubulin + ), located within a rosette of multiciliated ependymal cells, labeled with N-Cadherin [30,31]. Kidins220-floxed (Kidins220 f/f ) mice have been described previously as a hypomorphic model of Kidins220 and display reduced levels of Kidins220 when compared to control mice in different tissues [23]. SEZ homogenates from Kidins220 f/f also showed Kidins220 protein downregulation (Fig.…”

“…10.523252 doi: bioRxiv preprint pathways to promote neuronal survival, differentiation, and synaptic activity [12,13], and acts as a regulator of nervous system development [14,15]. KIDINS220 expression is altered in cancer and in neurological and neurodegenerative disorders, including cerebral ischemia, Alzheimer's disease, Huntington´s disease and idiopathic normal pressure hydrocephalus [16][17][18][19][20][21][22][23].…”

The pathogenesis of idiopathic normal pressure hydrocephalus based on the understanding of AQP1 and AQP4

“…The Kidins220–SNX27–retromer–AQP4 pathway was discovered as a regulatory mechanism for brain AQP4 expression and its participation in brain ventricular enlargement and hydrocephalus by Puerto et al We detected an unexpected relationship between SNX27-retromer downregulation and AQP4 lysosomal degradation caused by the loss of Kidins220, as well as a dramatic drop in Kidins220 and AQP4 expression at the ependymal barrier in patients with iNPH (Del Puerto et al, 2021 ).…”

Multiomic Approach Characterises the Neuroprotective Role of Retromer in Regulating Lysosomal Health

“…4C, Extended Data Fig. 4C) A number of these cargoes, for example SEMA4B/C, NOTCH1/2, NETO2 and KIDINS220, regulate essential neuronal pathways such as axonal guidance 47,48 , and synaptic transmission [49][50][51] , and are associated with neuronal disease and disorders 52,53 . These data underscore the protective role of Retromer in regulating the integrity of the plasma membrane proteome alongside maintaining lysosomal function.…”