Wallerian degeneration

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Wallerian degeneration is the process that happens after a nerve is cut or crushed. The part of the axon far from the nerve cell body (the distal part) breaks down and is cleared away. A related process, called Wallerian-like degeneration, happens in some brain and nerve diseases when the axon’s transport system isn’t working properly (for example in ALS and Alzheimer’s disease). A key early event for degeneration seems to be low levels or activity of a protein called NMNAT2, and a protein called SARM1 that can trigger the breakdown of the axon’s energy supply (NAD+).

What happens after injury
- The distal axon segment becomes damaged and then degenerates. This usually starts within about a day and a half after injury.
- The axon’s internal skeleton falls apart and the axonal membrane breaks.
- Myelin, the insulating layer around the axon, is degraded and removed.
- Macrophages and Schwann cells clear the debris. Schwann cells also respond to injury by changing, proliferating, and preparing a setup that helps new growth.

Schwann cells and the guiding tubes
- Schwann cells quickly react to axonal injury. They dedifferentiate, multiply, and organize into structures called Bungner bands, which guide regenerating axons.
- They release signals and growth factors that attract new sprouts from the proximal (cell-body–side) stump. If a sprout reaches a Bungner band, it can grow along the band and extend about 1 mm per day toward its target.

Regeneration: differences between the PNS and CNS
- Peripheral nervous system (PNS): Regrowth is relatively efficient. If the injury is near the end of the nerve, recovery can be nearly complete. If there’s a gap or scar tissue, doctors can help guide regrowth with surgical or other interventions.
- Central nervous system (CNS, including the spinal cord): Regeneration is slow or often fails. Myelin in the CNS is made by oligodendrocytes, not Schwann cells, and these cells don’t clean up debris as effectively. Myelin debris stays in the CNS longer and can inhibit regrowth. The CNS also forms glial scars that further hinder regeneration. Microglia (the brain’s immune cells) take longer to clean up debris than macrophages do in the PNS, contributing to slower repair.

Myelin clearance and barriers
- In the PNS, myelin debris is cleared quickly thanks to Schwann cells and invading macrophages. The blood-nerve barrier becomes more permeable after injury, helping immune cells reach the injury site.
- In the CNS, clearance is slower. Oligodendrocytes don’t recruit macrophages well to debris, and the blood–brain barrier limits immune access, so myelin debris can linger and block regeneration.

Growth factors and guidance
- After injury, nerve growth factors rise in the injured area. Schwann cells and nearby fibroblasts produce nerve growth factor (NGF) and other neurotrophic factors like BDNF, GDNF, CNTF, IGF, and FGF. Together, these help create a supportive environment for axon growth.
- Schwann cells also create physical guides (Bands of Bungner) and increase adhesion molecules on their surface to help new axons grow in the right direction.

What controls degeneration and protection
- A well-known mouse model (the WldS or Wlds mutation) shows delayed Wallerian degeneration, sometimes by around two to three weeks. This delay is linked to a region of the protein that increases NAD+ production and may alter how quickly Schwann cells and macrophages respond. The effect seems to be more about protecting the axon itself rather than slowing immune cells.
- A central player in degeneration is the SARM1 protein. When SARM1 is activated, it rapidly lowers NAD+ levels in the injured distal axon, triggering degeneration. NMNAT enzymes help prevent SARM1 activation, linking axon survival to the balance of these molecules. Deleting SARM1 in animals can protect axons after injury, highlighting a potential target for therapies.

In short
Wallerian degeneration is an active, regulated process that follows nerve injury. In the PNS, debris is cleared and regrowth can be quite effective, while in the CNS, debris clearance is slower and regrowth is limited. The process involves a dance between axon breakdown, myelin clearance, and the actions of Schwann cells, macrophages, microglia, and a network of growth factors. Understanding the roles of NMNAT2, SARM1, and related pathways offers potential ideas for treatments that slow degeneration and promote regeneration after nerve injury.