Tissue transglutaminase modulates pain but not neuronal survival after nerve injury

Aim: Tissue transglutaminase [transglutaminase 2 (TG2)] is implicated in central neuronal apoptosis and is expressed in the peripheral nervous system; however, its role in sensory neuron survival and neuropathic pain after nerve injury remains poorly defined. This study examined whether TG2 knockout (KO) affects dorsal root ganglion (DRG) neuron survival and pain-related behaviors following sciatic nerve injury. Methods: TG2 KO mice and wild-type (WT) controls underwent complete sciatic nerve transection (axotomy). Pain-related behavior was evaluated using detailed autotomy scoring over 14 days. DRG neuron survival was assessed using unbiased stereological counts. Results: TG2 KO resulted in a distinct, previously unreported “atypical autotomy” pattern, with lesions localized mainly to the midplantar paw region. In contrast, WT mice exhibited typical autotomy directed primarily at the toes. Despite this clear difference in pain phenotype, stereological analysis revealed that TG2 KO did not alter neuronal counts in intact or axotomized DRGs, with both groups showing comparable, significant neuronal loss after injury. Conclusions: These findings indicate that TG2 functions as an important modulator of neuropathic pain but is not required for neuronal survival in the adult DRG following nerve injury.