Disrupted Vitamin D Signaling and Metabolism in Neurodevelopmental and Neurodegenerative Disorders

Vitamin D is a secosteroid hormone with myriad physiological functions, including pleiotropic effects in the central nervous system. Vitamin D deficiency has been linked to multiple neurodevelopmental and neurodegenerative diseases, including Rett syndrome, epilepsy, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Over the past decades, vitamin D supplementation has been used as a preventative measure or a therapeutic intervention, often with inconsistent or variable responses. We discuss the known association between vitamin D deficiency and neurological disorder occurrence or progression for these disorders. Further, we assess the underlying causes for disruptions in vitamin D levels and the potential mechanisms of vitamin D-mediated improvements. We discuss disruptions in the vitamin D metabolism pathway, signaling, and/or feedback homeostasis that could underpin individual responses to vitamin D supplementation in these disorders. We further discuss the intersection between the vitamin D and cholesterol synthesis pathways and neuroinflammation, and the complex interactions that could contribute to the broad impact of vitamin D on neurological disorders.