Diabetes increases SCO-spondin secretion but reduces Wnt5a interaction with ependymal cells, inducing ciliary stiffness and Frizzled-2 downregulation
Year: 2025
Type: article
Abstract: Diabetes is a chronic metabolic disorder with systemic complications. Hyperglycemia damages multiple organs, including the brain, increasing the risks of stroke, dementia, and oxidative stress. Diabetes is also linked to ventricular enlargement in the human brain. Here, we examine how diabetes alters the secretion of subcommissural organ spondin (SCO-spondin) and Wnt5a by SCO cells, which subsequently affects ependymal ciliary beating and cerebrospinal fluid (CSF) circulation. Under diabetic conditions, SCO-spondin secretion by SCO cells increased. CSF-borne SCO-spondin was observed interacting with ependymal cilia, which showed increased stiffness. Control SCO cells were Wnt5a-positive, indicating active biosynthesis and secretion; in contrast, Wnt5a immunostaining was negative under diabetic conditions, and its interaction with ependymal cells decreased. Additionally, the Wnt5a receptor Frizzled-2 and the proteoglycan testican, essential for Wnt5a-receptor engagement, were not detected in ependymal cells during diabetes. To further explore downstream changes, we examined aquaporin-4 (AQP4) in control and diabetic samples and found condition-dependent differences in its subcellular distribution within ependymal cells. Accordingly, peri-ependymal edema and periventricular lucency were observed. Conversely, GLUT1, MCT2, and Cx-43 remained unchanged, suggesting that diabetes selectively modifies specific ependymal properties. Proteomic analysis of CSF from diabetic patients confirmed the presence of spondin-1 and thrombospondins, which may replace SCO-spondin in humans. Overall, these findings support a model where increased SCO-spondin release and decreased Wnt5a-Frizzled-2-testican signaling in ependymal cells promote ciliary stiffening and periventricular edema in the diabetic brain.
Source: Neurobiology of Disease
Authors: Manuel Cifuentes, Eder Ramírez, María José Barahona, Fernando Martínez, Isabelle de Lima, Luciano Ferrada, Romina Bertinat, Felipe Ávila, Natalia Saldivia, Margarita Pérez-Martín, Begoña Oliver-Martin, Nicolás Ciano-Petersen, María del Mar Fernández-Arjona, Katterine Salazar, Francisco Nualart
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,180
Awards: OXIDIZED VITAMIN C SENSITIZES CANCER CELL TO FERROPTOSIS, MEDIAN EMINENCE HYPOTHALAMIC AREA INVOLVED IN THE RAPID TRANSFER OF GLUCOSE TO THE BRAIN FUNCTIONAL AND CELLULAR MECHANISM., TRANSCRIPTOME ANALYSES REVEAL THE BASIS OF SIGNAL TRANSDUCTION INVOLVED IN COPPER TOLERANCE IN THE MARINE ALGA ULVA COMPRESSA (CHLOROPHYTA) USING NEXT GENERATION SEQUENCING TECHNOLOGIES, EFECTO DE LA VITAMINA C SOBRE LA PLASTICIDAD DE LA CELULA TRONCAL TUMORAL DE GLIOBLASTOMA Y EPENDIMOMA, IIIG9 EXPRESSION AND FUNCTION DURING THE DIFFERENTIATION AND POLARIZATION OF EPENDYMAL CELLS AND IN EPENDYMOMA PROGRESSION, THE PHOSPHATASE REGULATORY PROTEIN IIIG9 MODULATES RADIAL GLIA DIFFERENTIATION AND EPENDYMOMA CELL MIGRATION., OXIDIZED VITAMIN C AN ACTIVATOR OF MOTOR NEURON NEURITES DEGENERATION AND CELL DEATH IN AMYOTROPHIC LATERAL SCLEROSIS, SISTEMA DE LA GLUCOSA 6 FOSFATASA EN TANICITOS HIPOTALAMICOS IMPLICANCIAS EN LA FISIOLOGIA Y FISIOPATOLOGIA DE LA DIABETES TIPO 2., G7555519474, VITAMIN C RECYCLING FUNCTIONAL EFFECTS IN NEURONAL DIFFERENTIATION AND NECROPTOSIS INDUCTION
OpenAlex ID: W4417443935