Since inhibition of TGMs in Smox/Sat1-dKO mice prevents cerebellar injury and ataxia, our findings suggest that an aberrant spermine-TGM2-α-Synuclein-neuroinflammatory circuit is sufficient to provoke Purkinje cell damage, gliosis, and white matter demyelination in Smox/Sat1-dKO mice, and that this circuit may play an important role in other forms of neurodegeneration. Here, SAT1 is linked to cerebellar ataxia.