Multifaceted roles of S100A6 in neurological disorders: expression, interaction networks, and clinical implications

S100A6 (calcyclin) is a multifunctional Ca²⁺/Zn²⁺-binding protein of the S100 family, widely expressed in neurons and glia with a developmentally regulated and cell-type-specific pattern. This review synthesizes current knowledge on its roles in the nervous system. We detail its complex interactome, which includes cytoskeletal regulators, molecular chaperones, nuclear transport proteins, and cell surface receptors, positioning S100A6 as a central signaling hub. Furthermore, we examine its dynamic and context-dependent involvement in major neurological disorders. In Alzheimer's disease and amyotrophic lateral sclerosis, it functions as a glial-derived factor linking protein aggregation, metal dyshomeostasis, and neuroinflammation. In neuro-oncology, S100A6 exhibits dual roles, acting as a promoter of malignancy and immunosuppression in glioblastoma, an epigenetically silenced marker in medulloblastoma, and a diagnostic aid for peripheral nerve sheath tumors. Its expression is also altered in epilepsy, traumatic brain injury, and autoimmune encephalitis. Understanding the nuanced functions of S100A6 offers significant potential for developing novel diagnostic biomarkers and targeted therapeutic strategies for a range of challenging neurological conditions.