Disruption of the ganglioside-plasma membrane calcium ATPase-neuroplastin nexus leads to impaired calcium homeostasis in glioblastoma

Abstract

Glioblastoma (GBM), an exceedingly invasive brain tumor, is characterized by the disruption of multiple signaling pathways, particularly those governing calcium homeostasis. Additionally, cell membranes in GBM exhibit altered lipidomic profiles, especially complex sialoglycans gangliosides, which affect plasma membranes both structurally and functionally. In this work we show a disruption of a plasma membrane molecular triad composed of gangliosides, neuroplastin (Np), and plasma membrane calcium ATPase (PMCA) in GBM, leading to a severely diminished PMCA activity. Our transcriptomic, epigenetic, proteomic, lipidomic, and in silico analyses consistently demonstrated downregulation of Np and PMCA isoforms both at mRNA and protein levels in our GBM cohort, in agreement with a broader trend observed in public datasets. Analysis of the uniquely changed GBM ganglioside profile in the context of PMCA and Np expression and PMCA activity reveals GD3 as a key molecular determinant of reduced PMCA activity in GBM samples. In contrast, GD1b, necessary for optimal PMCA function in healthy tissue, is significantly reduced in GBM. Our findings establish the gangliosides-PMCA-Np nexus as a crucial complex involved in calcium signaling in GBM, contributing to GBM etiology and progression.