This is a mechanism module, not a disease. Do not create a Disease entry for Wallerian degeneration or for traumatic axonal injury as such; those are mechanisms inside a disorder entry. Disorder entries reference individual nodes via conforms_to, for example "focal_axonal_injury_wallerian_degeneration#SARM1 Activation and Axonal NAD+ Depletion".
What conformers substitute at the trigger node: traumatic brain injury substitutes high-strain-rate stretch and shear of white matter axons during rapid head acceleration; spinal cord injury substitutes contusion or laceration of ascending and descending tracts; peripheral nerve injury substitutes crush or transection of a named nerve, with the Schwann cell (CL:0002573) and the distal nerve stump as the site; inflammatory demyelinating disease substitutes immune-mediated transection of axons inside a lesion. The locations substituted at the downstream nodes follow the compartment: brain white matter and corpus callosum for traumatic brain injury, spinal cord white matter for spinal cord injury, the peripheral nerve for nerve injury. A conformer that models regeneration (peripheral nerve, where the distal stump is cleared and reinnervated) extends the chain past the consequence node rather than altering it.
Worked conformers to come: Traumatic_Brain_Injury (diffuse axonal injury branch) and Chronic_Traumatic_Encephalopathy (repetitive mild injury, whose trauma node is mostly axonal). Neither is wired to this module yet; this module was created first in the build order of the injury-granularity pilot.
Evidence asymmetry to be aware of when conforming: the trigger, transport interruption, and Wallerian-degeneration nodes all carry human postmortem evidence, whereas the NMNAT2 and SARM1 steps rest mainly on mouse genetics and neuronal culture. The one human genetic observation on the pathway is biallelic NMNAT2 loss of function in fetal akinesia. This is recorded as a HUMAN_MODEL_MISMATCH discussion rather than left implicit, and it is the reason the central effector node's claim is framed as the executing step of the cascade rather than as a validated human therapeutic target.
Does the SARM1-dependent execution step, established in mouse genetics and neuronal culture, operate in human focal axonal injury?
HUMAN MODEL MISMATCH
OPEN
focal_axon_injury_sarm1_human_validity
Attached to:
SARM1 Activation and Axonal NAD+ Depletion
Loss of Axonal NMNAT2
The trigger, transport-interruption and Wallerian-degeneration nodes of this module all carry human postmortem evidence. The two molecular nodes do not: the demonstrations that NMNAT2 loss licenses degeneration and that SARM1 executes it come from mouse knockouts and from rodent neuronal culture, and the traumatic-injury experiments are closed-head and impact-acceleration models in mice. The one human observation on the pathway is biallelic NMNAT2 loss of function in two fetuses, which is a germline deficiency rather than a focal lesion. So the human question is not whether axons degenerate distal to a lesion - that is directly observed - but whether the SARM1 NADase is the executing step in human axons, which matters because it is the step the candidate drugs act on. Resolving it needs SARM1-dependence evidence in human neurons or human tissue, or a clinical result with a SARM1 inhibitor.
Focal Axonal Injury
trigger
An axon is damaged at one point along its length. The insult may be mechanical - stretch and shear at high strain rate, crush, or outright transection - or an inflammatory attack on the axon inside a lesion. What the cascade requires is only that the damage be focal: the lesion defines a proximal segment that remains attached to the cell body and a distal segment that does not, and the module describes the fate of the distal segment. Axon length is not a determinant here, which is what separates this trigger from the diffuse metabolic insults of the dying-back modules.
Downstream
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Axonal Transport Interruption and Axonal Swelling
Focal injury damages the axonal cytoskeleton at the lesion, and the microtubule tracks that carry transported cargo are broken there.
Show evidence (3 references)
"Axons undergo Wallerian degeneration distal to a point of injury."
States the geometry this trigger node asserts: injury at a point, and degeneration of what lies distal to it. Human postmortem spinal cords after traumatic spinal cord injury and cerebral infarction.
"Similar axonal undulations and varicosities were observed following TBI in humans, suggesting primary microtubule failure may also be a feature of DAI."
Human brains acquired acutely after traumatic brain injury show the same focal axonal lesions as mechanically stretched axons in culture, establishing mechanical injury of white matter axons as a real human trigger.
"Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions."
Establishes the non-mechanical entry point to this module: inflammatory lesions transect axons in human multiple sclerosis, so the trigger node is not specific to trauma.
Axonal Transport Interruption and Axonal Swelling
amplifier
Cytoskeletal failure at the lesion interrupts anterograde axonal transport. Transported cargo accumulates where transport stops, producing the swellings and terminal retraction bulbs that are the histological signature of traumatic axonal injury. Amyloid precursor protein is the cargo conventionally stained for this purpose, which is why beta-APP immunoreactivity marks damaged axons in injured human white matter. Because an axon contains many microtubules, breakage of a subset interrupts transport only partly and at several points, giving the periodic varicosities seen alongside frank bulbs.
Downstream
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Loss of Axonal NMNAT2
NMNAT2 reaches the axon only by anterograde transport and has a short half-life, so interrupting its delivery is sufficient to deplete it beyond the lesion.
Show evidence (3 references)
"In addition, beta APP immunoreactivity was noted within white matter tracts where it marked damaged axons."
The original human postmortem demonstration that accumulated amyloid precursor protein marks injured axons in white matter after head injury, which is what makes cargo accumulation the standard histological readout of this node.
"Although transport interruption underlies axonal bulb formation, it is unclear how varicosities arise, with multiple sites accumulating transported materials along one axon."
States the mechanism of this node - transport interruption accumulating transported material - and distinguishes the terminal bulb from the periodic swellings along the shaft. Quoted from the stretch-injury culture model that produced the microtubule data.
"After stretch, undulating distortions formed along the axons that gradually relaxed back to a straight orientation, demonstrating a delayed elastic response. Subsequently, swellings developed, leading to degeneration of almost all axons by 24 h."
Shows the temporal order within this node: cytoskeletal distortion first, then swellings, then degeneration of nearly every axon within a day.
Loss of Axonal NMNAT2
amplifier
NMNAT2 is the NAD+-synthesising enzyme that maintains the axon, and it is the most labile of the three mammalian NMNAT isoforms. Because it is made in the cell body and delivered by anterograde transport, the segment beyond a focal lesion loses it within hours of injury, before any morphological degeneration is visible. Neither NMNAT1 nor NMNAT3 substitutes. Depleting NMNAT2 is itself sufficient to make an uninjured axon degenerate, so this node is not merely a correlate of injury but the step that licenses the next one.
Downstream
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SARM1 Activation and Axonal NAD+ Depletion
Falling NMNAT2 activity is what permits SARM1 to become active; the degeneration caused by NMNAT2 depletion does not occur without SARM1.
Show evidence (3 references)
"Nmnat2 is by far the most labile Nmnat isoform and is depleted in distal stumps of injured neurites before Wallerian degeneration begins."
Establishes both halves of this node: NMNAT2 is the labile isoform, and it disappears from the distal stump ahead of degeneration, so its loss is upstream rather than a consequence.
"Axons require a constant supply of the labile axon survival factor Nmnat2 from their cell bodies to avoid spontaneous axon degeneration."
Confirms the continuous-supply requirement independently, in sympathetic neuron cultures with live imaging of NMNAT2 transport.
"These data indicate a previously unknown role for NMNAT2 in human neurological development and provide the first direct molecular evidence to support the involvement of Wallerian degeneration in a human axonal disorder."
The only human genetic evidence on this step: biallelic NMNAT2 loss of function in two fetuses, with the authors reading it as involvement of Wallerian degeneration in human disease. Indirect for the injury cascade, because the lesion here is germline rather than focal.
SARM1 Activation and Axonal NAD+ Depletion
central effector
SARM1 is the executioner of the cascade. Once NMNAT2 support falls, SARM1 is activated and its TIR domain hydrolyses NAD+ directly, collapsing axonal NAD+ and the energy state that depends on it. The destruction is local to the axon and does not require the cell body. This is the key conformance target of the module: it is the rate-limiting step, it is where every entry route converges, and it is the only step in the chain with a candidate drug target, since both genetic deletion and selective NADase inhibitors block degeneration downstream of an injury that has already happened.
Downstream
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Wallerian Degeneration of the Distal Axon
NAD+ destruction is the act of dismantling; the distal axon fragments because SARM1 has consumed the cofactor it needs to persist.
Show evidence (5 references)
"We report that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD(+)) after injury."
States the node's claim directly - SARM1 activation after injury destroys axonal NAD+ locally - using protease-sensitised SARM1 in dorsal root ganglion neuron cultures.
"Using traumatic and vincristine-induced injury models in neurons, we demonstrate that the NADase activity of full-length SARM1 is required in axons to promote axonal NAD+ depletion and axonal degeneration after injury."
Identifies the enzyme activity bound in this node: SARM1's own TIR domain cleaves NAD+, and that activity is required in the axon for depletion and degeneration. Purified proteins plus neuronal injury models.
"Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals."
The loss-of-function evidence that makes this the rate-limiting node: without SARM1 a severed axon survives for weeks, so the cascade cannot proceed past this step.
+ 2 more references
Wallerian Degeneration of the Distal Axon
effector
The segment of axon distal to the lesion is dismantled: neurofilament compaction, accumulation of organelles, granular disintegration of the cytoskeleton, fragmentation into ovoids, and breakdown of the surrounding myelin, followed by clearance. This is a programmed self-destruction and not passive wasting from the loss of cell-body support, which is the point the SARM1 and NMNAT2 genetics above establish. In the human central nervous system the process is slow, continuing for months to years, and ends in an astrocytic scar rather than in regeneration.
Downstream
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Disconnection of Neural Circuits
An axon is the physical connection between two regions, so destroying the distal segment removes that connection.
Show evidence (3 references)
"Neurofilament (NF) staining demonstrated a spatio-temporal pattern of axonal loss within degenerating descending nerve fibre tracts that could be detected close to the lesion as early as 12 days after injury and progressed to an almost complete loss of NF immunoreactivity at survival times of 1..."
Human timecourse of this node in the central nervous system: axonal loss in the tract distal to the lesion, beginning within two weeks and essentially complete by a year.
"Several morphological features such as neurofilament compaction, accumulation of organelles and inclusions, axoskeletal flocculation, myelin degeneration and formation of ovoids are similar to profiles encountered in classical examples of WD."
Supplies the ultrastructural description of this node and identifies the morphology after traumatic axonal injury as that of classical Wallerian degeneration.
"Our results provide direct evidence that axons actively promote their own destruction after injury and identify dSarm/Sarm1 as a member of an ancient axon death signaling pathway."
Supports the characterisation of this node as programmed self-destruction rather than passive loss of trophic support, which is what licenses calling it an effector step with a drug target upstream.
Disconnection of Neural Circuits
consequence
The convergent outcome is loss of connectivity. Axons destroyed distal to their lesions no longer transmit, the white matter tracts they composed thin and degenerate, and the networks they linked are measurably disconnected. Which deficit follows depends entirely on which tracts were injured, so this node is deliberately described as disconnection rather than as any particular clinical syndrome; conforming entries attach their own phenotypes here. In humans after a single traumatic brain injury the degeneration continues for years, so this node is not restricted to the acute phase.
Show evidence (3 references)
"Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury."
Human postmortem measurement of the tissue-level consequence: the corpus callosum, a tract composed of the axons this module destroys, is a quarter thinner in long-term survivors of a single injury.
"Graph metrics were significantly associated with cognitive performance: information processing speed (R(2) = 0.64), executive function (R(2) = 0.56) and associative memory (R(2) = 0.25)."
Quantifies the consequence in patients: measures of structural connectivity derived from white matter tracts track cognitive performance after traumatic brain injury.
"the slow reduction of CNS myelin and the long-term deposition of a dense astrocytic scar may present an environment that is non-supportive for axon regrowth"
Explains why the disconnection persists in the central nervous system: the degenerated tract is replaced by a scar that does not support regrowth, so the lost connection is not restored.