Oligodendroglial TANGO2 Regulates Lipid Metabolism to Control Motor Coordination

TANGO2 deficiency disorder (TDD) is a rare genetic disease caused by mutations in the TANGO2 gene, characterized by prominent neurological symptoms. However, the pathological mechanisms underlying TANGO2 loss-of-function in neurologic symptoms remain unknown. Here, we generated constitutive and cell-type-specific Tango2 knockout mouse models to examine TANGO2's role in the central nervous system (CNS). Behavioral analyses revealed that both constitutive and oligodendrocyte-specific deletion of Tango2 recapitulate the motor deficits associated with individuals with TDD. Morphological quantifications further showed that Tango2 deletion led to robust cerebellar myelin loss and an increase in synapse number in the cerebellar cortex. In addition, transcriptional analysis and lipidomic profiling demonstrated that Tango2 deletion downregulated key processes involved in phospholipid metabolism. Significantly, vitamin B5 supplementation alleviated motor deficits and cerebellar myelin defects in Tango2 knockout mice. Overall, our findings establish that TANGO2 is essential for maintaining normal motor behaviors by regulating lipid metabolism in oligodendroglia.