Axonal degeneration is a prominent feature of many forms of neurodegeneration, and is also an early event in blast-mediated TBI, the signature injury of soldiers in Iraq and Afghanistan. It has not been known, however, whether this axonal degeneration is what drives development of subsequent neurologic deficits after the injury. Wallerian degeneration slow strain (WldS) of mice are resistant to some forms of axonal degeneration by virtue of a triplicated fusion gene encoding the first 70 amino acids of Ufd2a, a ubiquitin-chain assembly factor, that is linked to the complete coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (NMAT1). Here, we demonstrate that resistance of WldS mice to axonal degeneration after blast-mediated TBI is associated with preserved function in hippocampal-dependent spatial memory, cerebellar-dependent motor balance and retinal and optic-nerve dependent visual function. Thus, early axonal degeneration is likely a critical driver of subsequent neurobehavioral complications of blast-mediated TBI. Future therapeutic strategies targeted specifically at mitigating axonal degeneration may provide a uniquely beneficial approach to treating patients suffering the effects of blast-mediated TBI.
Significance Statement Blast-mediated traumatic brain injury (TBI) is the signature injury of soldiers associated with chronic cognitive, motor and visual dysfunction. An early event in blast-TBI is diffuse axonal damage, but it has not been known whether this drives development of subsequent pathology. WldS mutant mice are resistant to axonal degeneration via a mutation that enables maintenance of neuronal NAD levels after injury, and a number of different approaches have been proposed for augmenting NAD levels in the nervous system. We show that WldS mice are protected from axonal degeneration and deficits in cognition, movement and vision after blast-TBI. Axonal degeneration is thus a critical early event in this prevalent injury, suggesting therapeutic potential of specifically mitigating early axonal degeneration after blast-TBI.
Authors report no conflict of interest.
This work was supported by funds from Calico LLC (California Life Company), and from an anonymous donor to the Mary Alice Smith Fund for Neuropsychiatry Research to A.A.P.