Wallerian Degeneration
Wallerian Degeneration: Principles & Features
- Wallerian degeneration: Definition
- Sequence of axonal and myelin degeneration
- Location: Segment of nerve distal to a site of transection
- Associated with inflammation: Macrophage-predominant
- ? Similar process: Dying back axonal degeneration
- Morphological & other changes in nerve constituents
- Stimulus for Wallerian degeneration: Distal axon loses connection with proximal axon
- Early change (Hours): Accumulation of organelles & mitochondria in paranodal regions near injury
- Endoplasmic reticulum: Loss of structure
- Neurofilaments: Degradation associated with influx of Ca++ & activation of calpain
- Mitochondria: Swelling
- Axon: Becomes fragmented; Phagocytosed
- Myelin
- Early: Widening of Schmidt-Lantermann incisura; Ovoid formations begin at these loci
- Paranodal myelin retraction
- Myelin "collapse": Forms ovoids
- Degenerative changes occur: Distal to proximal direction; Small axons before large axons
- Schwann cells
- Proliferate
- Form Bands of Bungner
- Definition: Arrays of Schwann cells & processes within basement membrane
- Provide substrate for axonal regeneration
- Schwannn cells atrophy and disappear if axonal regeneration does not occur
- Phagocytes: Mostly incoming hematogenous macrophages
- Invasion of nerve 3 to 4 days after transection
- Phagocytosis of sudanophilic (lipid) debris: Appear as foamy cells
- Complement is necessary for phagocytosis
- Course: Cells may persist for 3 to 7 months
- Fibroblasts
- Proliferate during 1st week
- Migrate adjacent to degenerating fibers
- Produce some collagen
- Blood-nerve barrier
- Loses integrity during early degeneration & regeneration
- Re-established over months
- Timing
- Degeneration begins several days (4 to 10) after axonal transection
- Before degeneration the distal axon segment may remain electrically excitable
- Molecular events1
- Early in axons: Loss of m-Calpain; Ca++ entry
- Associated cytokines
- Early: TNFα and IL-1α
- After delay: IL-1β
- Inhibitory molecule: OX2 (CD200)
inhibits macrophage lineage cells
- Not related to bcl-2 or caspase activation
- Molecules upregulated in neurons after axotomy
- STAT-3 protein
: Associated with CNTF stimulation
- Activating transcription factor 3
: Acts as heterodimer with jun proteins
- Nna1 (ATP/GTP-Binding protein 1; AGTPBP1)
: Motor neurons
- Putative zinc carboxypeptidase
- Presumed nuclear localization
- Adenosine triphosphate/guanosine triphosphate binding motif
- Mutations: Purkinje cell degeneration (pcd) mouse
- Nerve injury associated kinase: Sensory neurons
- Molecules upregulated in nerve distal to transection
- Early activation of erbB2: Related to Schwann cell demyelination after axotomy4
- Time course
- Early activation: Occurs 10 to 180 minutes after nerve damage
- erbB2 also increased late (days) after nerve transection
- Anatomy
- Originates in microvilli of Schwann cells, in direct contact with axon
- Localized to nodal region of myelinating Schwann cells
- Activation occurs near & distal to nerve transection site
- Related features
- MAPK is also activated early after nerve transection
- ATP mimetic PKI166 (Blocks erbB2 activation): Reduces ovoid accumulation in Schwann cell cytoplasm
- Neuregulin coreceptor erbB3 participates in the rapid activation
- Neuregulin in vitro: Induces demyelination mimicking the early response of Schwann cells to nerve damage
- Ninjurin1
- Adhesion molecule
- Induced in injured DRG neurons & Schwann cells
- Ninjurin2
- Adhesion protein
- Expressed constitutively by mature sensory neurons
- Induced in Schwann cells in distal segment of lesioned nerve
- Glial cell line-derived neurotrophic factor (GDNF) &
GDNF family receptor α1 (GFRα1)
- Disintegrin CRII-7/rMDC15
:
ADAM (a disintegrin and metalloprotease) gene family
- FGF-2
- IL-6: Pain-inducing cytokine
- TNF-α
: Macrophage recruitment from the periphery
- SDF-1γ (Stromal cell-derived factor (SDF)-1 isoform)
- Mice with slow Wallerian degeneration
- C57BL/Wlds
- Genetics
- Mutation: 85 kb tandem triplication on distal mouse chromosome 4
- Mutated region contains 2 associated genes
- Nicotinamide mononucleotide adenylyltransferase (NMNAT1; D4Cole1e)
- 5' end of ubiquitination factor E4B (Ube4b)
- Proteins
- NMNAT1
- Subcellular location: Nuclear
- Expressed in: Skeletal muscle, Heart, Liver, Kidney & Brain
- Function: NAD biosynthesis
- Probably the component responsible for axonal protection
- Sirt1
(NAD-dependent deacetylase),
downstream of Nmnat, contributes to axonal protection
- E4B
- Subcellular location: Cytoplasmic
- Expressed in: Skeletal muscle, Ovary, Testis & Heart
- Function: Binds to ubiquitin moieties of conjugates; Catalyzes ubiquitin chain assembly
- Mutation effects on proteins: Increased expression
- Mouse effects
- Wallerian degeneration delayed by 3 to 4 weeks
- Axons less susceptible to vincristine toxicity
- pmn mouse: Slower progression of disease
- SOD1/ALS (SOD1-G93A) mouse: Slightly longer survival; Delayed denervation at NMJ3
- Neuronal nitric oxide synthase knockout2
- Slow Wallerian degeneration
- Delayed regeneration
- Incomplete pruning of axon sprouts: Enhanced number of axons
Wallerian Degeneration: Pathology
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