Traumatic Axonal Injury: Mechanisms and Translational Opportunities

Abstract

Traumatic axonal injury (TAI) is an important pathoanatomical subgroup of traumatic brain injury (TBI) and a major driver of mortality and functional impairment. Experimental models have provided insights into the effects of mechanical deformation on the neuronal cytoskeleton and the subsequent processes that drive axonal injury. There is also increasing recognition that axonal or white matter loss may progress for years post-injury and represent one mechanistic framework for progressive neurodegeneration after TBI. Previous trials of novel therapies have failed to make an impact on clinical outcome, in both TBI in general and TAI in particular. Recent advances in understanding the cellular and molecular mechanisms of injury have the potential to translate into novel therapeutic targets.

Keywords: axon; brain; degeneration; injury; therapeutics; traumatic.

Figure 1

Traumatic Brain Injury Subtypes. There are several different variants of traumatic brain injury, which often coexist and have significant overlap. They can be broadly divided into focal and diffuse injuries, although it is worth noting that true focal injuries are rare and blast injuries lack a pure neuropathological correlate. The clinical presentation and prognosis of a traumatic brain injury varies depending on the individual nature of the injury. The inherent variability makes it challenging to establish the optimal treatment and there is recognition of the value of an individualised approach.

Figure 2

Cellular and Molecular Activities Resulting in Secondary Brain Injury. Following a traumatic insult to the brain, an extensive series of various cellular processes is initiated that leads to further neuronal dysfunction and death. This contributes to the complexity of traumatic brain injury but also provides a variety of therapeutic targets.

Figure 3

Key Figure: Summary of Molecular Mechanisms and Therapeutic Targets in Traumatic Axonal Injury (TAI) Mechanical stretch leads to undulation of the axon and activation of various injury pathways. Direct membrane mechanoporation and opening of exchange channels leads to calcium influx. This activates calpains, which degrade structural proteins. Proinflammatory cytokines have broad effects including initiation of caspase-mediated proteolysis and microglia recruitment. Calcium influx also triggers generation of the mPTP, with subsequent solute influx and mitochondrial dysfunction/death. Reactive oxygen species are generated and result in oxidative damage. Neurofilaments compact and aberrant proteins including TDP43 and amyloid fibrils accumulate. Microtubules are fractured; this leads to impairment of axonal transport with failure to deliver nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and subsequent Wallerian degeneration. Eat-me signals including phosphatidylserine are externalised and may initiate phagoptosis of stressed neurons by microglia. Note that although NMDA channels are shown on the axon for simplicity, most are localised on dendrites and dendritic spines and axonally based channels are in a minority. Abbreviations: TDP43, transactive response DNA-binding protein 43 kDa (a nuclear-pore transport protein, the cytoplasmic mislocalisation and aggregation of which is associated with chronic traumatic encephalopathy, frontotemporal dementia and amyotrophic lateral sclerosis); NMDA receptor, a glutamate receptor/ion channel that is a channel for calcium ion flux. mPTP, mitochondrial permeability pore (when induced in mitochondria by tissue injury this allows solute influx, leading to mitochondrial swelling and death).