Neuronal CD1d deficiency causes sphingolipid dysregulation, early-onset Lysosomal Storage Disorder neuropathology and neurologic deficits

This study unveils a non-canonical function of CD1d beyond its role in immunity, where its known for presenting glycolipids to Natural Killer T (NKT) cells. Despite CD1d's reported expression in the brain and its function in preventing neuroinflammation through NKT cells, its impact on brain homeostasis has not been explored. Mice lacking Cd1d exhibit spontaneous ataxia, neuropsychiatric deficits (depression- and anxiety-like symptoms), and cognitive impairments accompanied by early-onset neurodegeneration. Additionally, they display tau hyperphosphorylation, Golgi abnormalities, demyelination, and lysosomal accumulation and dysfunction, resembling Lysosomal Storage Disorders neuropathology. Notably, the major features are recapitulated by CD1d deficiency specifically in neurons, revealing a central role in brain homeostasis. Sphingomyelinase treatment reverses the observed sphingolipid imbalance, lysosomal and autophagy defects, and neuronal death. This study breaks new conceptual ground, linking CD1d to brain integrity and offering new insights into the connection between immune gene dysfunctions and central nervous system disorders.