Single-Cell Transcriptomics Reveals that VDR TaqI/ApaI Risk Haplotypes Impair Remyelination by Disrupting Microglial Oligodendrocyte Crosstalk

Abstract

Background: The failure of spontaneous remyelination represents a critical therapeutic barrier in multiple sclerosis (MS) and other demyelinating pathologies. While genetic epidemiological studies have consistently linked Vitamin D Receptor (VDR) polymorphisms to disease susceptibility and severity, the specific cellular mechanisms translating these risk haplotypes into regenerative failure have remained unresolved. Methods: To deconstruct the demyelinated lesion microenvironment, we utilized high-resolution single-nucleus transcriptomics across distinct VDR genotypic cohorts (Risk vs. Wildtype). We integrated topological intercellular communication modelling to map shifts in local cellular crosstalk and employed computational pseudo time trajectory inference to evaluate the direct developmental consequences of genetic risk on the complete oligodendrocyte lineage. Results: Our analysis revealed a profound and targeted transcriptomic collapse of the RXRA heterodimer specifically within the resident microglial compartment of the VDR-Risk cohort. This intrinsic receptor uncoupling functionally neutralized the microglial neuroprotective state, resulting in a near-total cessation of Prosaposin (PSAP) secretion. Trajectory inference demonstrated that oligodendrocyte precursor cells (OPCs) deprived of this critical microglial PSAP-GPR37 trophic signalling axis suffered a severe developmental stall, structurally preventing their terminal maturation into functional, myelin-forming oligodendrocytes. Conclusions: These findings shift the pathophysiological paradigm of VDR genetic risk from generalized neuroinflammation to a highly targeted disruption of microglial oligodendroglia crosstalk. The RXRA-mediated PSAP-GPR37 signalling cascade is identified as a pivotal mechanistic vulnerability, offering a novel, targeted therapeutic pathway to overcome remyelination arrest.