Wallerian Degeneration: Principles & Features
- Wallerian degeneration: Definition
- Sequence of Axon & Myelin degeneration
- Location: Segment of nerve distal to a site of transection
- Stages
- Electrodiagnostic
- ? Similar process: Dying back axon degeneration
- Wallerian Degeneration: Morphological & other changes in nerve constituents
- Stimulus for Wallerian degeneration
- Distal axon loses connection with proximal axon
- Wallerian degeneration: Axon changes
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- Early
- Minutes: Changes in axon segments near transsection
- Short-distance (200 μM): Acute axon degeneration (AAD)
- Mediated by
- Extracellular Ca++ influx
- Anterogradely conduced wave in distal axon
- Activation of calpain
- Ca++-dependent serine-threonine protease
- Intracellular enzyme
- Inhibited by: Ca++ channel blockers
- Hours to 2 days
- Regions near injury: Accumulation of organelles & mitochondria
- Dystrophic bulbs
- Occur at both transected ends
- Mechanism: Anterograde & retrograde axon transport
- Proximal & Distal axon: Retraction from injury site
- Distal axon
- Remains morphologically intact & electrically excitable
- Axon transport (anterograde & retrograde) continues
- Proximal stump: Produces sprouts within hours after axotomy
- Later (≥ 3 days): Changes in distal axon
- Endoplasmic reticulum: Loss of structure
- Cytoplasm: Neurofilament & Cytoskeleton Degradation
- Associated with influx of Ca++
- Activation of calpain
- Autophagy-related
- Mitochondria: Swelling
- Distal axon morphology: Granular degeneration
- Becomes fragmented
- Phagocytosis
- Direction after focal injury: Proximal to Distal; Rate of up to 24 mm/hr
- Timing
- Before degeneration
- Distal axon segment may remain electrically excitable
- Sensory responses persist 2 to 3 days longer than motor
- Conduction failure may precede axon degeneration
- Time to loss of excitability
- Facial nerve: 4 to 7 days
- Arm nerves, Motor: 5 to 7 days
- Arm nerves, Sensory: 7 to 10 days
- Degeneration
- Begins several days (4 to 10) after axonal transection
- Progression
- Possible length dependence
- May be from proximal to distal axon or diffuse
- More rapid with shorter distal stump
- WD Delayed by: Molecules & Factors
- Temperature: Reduced
- Extracellular Ca++: Lowered
- Ca++ channel (L-type) blockers
- Mutations or Loss
- NMNAT1: WldS
- NMNAT2
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- General
- Chaperone
- Aids in refolding of misfolded proteins
- NAD+ biosynthesis
- Catalyzes
- Nicotinamide mononucleotide (NMN) →
Nicotinamide adenine dinucleotide (NAD+)
- Controls SARM1 activation
- NAD+: Inhibits SARM1 (Inactive TIR domains)
- NMN: Associated with SARM1 activation (Active TIR domains)
- Present in axon cytoplasm
- Carried down axon by anterograde axon transport
- Short half-life: Rapidly lost after axon transection
- 2 pools: Vesicular & Non-vesicular
- Axons
- Disease: Polyneuropathy & Erythromelalgia
- NOS knockout
- DR6 (TNFRSF21)
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- SARM1
(Inhibition)
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- Toll-like receptor adapter protein
- SARM1 structures
- Forms octameric ring: via SAM domain
- SARM1 Loss
- Axon degeneration: Slowed
- Types of axon degeneration affected
- Transsection
- Dying back (Chemotherapy)
- SARM1 activity
- Required for early injury induced axon degeneration
- Causes damage by: Reducing NAD+ in axon cytoplasm
- SARM1 activated by
- High NMN/NAD+ ratio
- TNF-α
(Neuro-Inflammatory signal)
- MLKL (Necroptosis-like signal): Via inducing loss of
- Axotomy
- Blocks delivery of labile axon survival factors (NMNAT2)
- Factors normally inhibit SARM1
- Mechanism of SARM1 action: Stimulates NAD+ cleavage & loss
- Active SARM1 protein domain
- Toll/Interleukin-1 receptor (TIR)
- Possesses intrinsic NAD+ cleavage (NADase) activity
- NADase activity increased
- NAD+ converted to ADPR (ADP Ribose) products
- Leads to Ca++ influx & Axon degeneration
- SARM1 required for: Vincristine & Bortezomib induced axon degeneration
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- Vincristine
- Stimulates axon autonomous degeneration via MAPK pathway
- Mediated by MAP3K12
& MAP3K13
- Bortezomib
- Induces axon degeneration via neuron cell body
- Mediated by
- Activated caspases (Caspase-3 cleavage) in axon
- Transcriptional regulation
- Apoptosis-like
- Similar mechanism to NGF withdrawal
- Disease association: ALS & SPG
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- Gain of function polymorphisms
- Frequency: 0.12% vs Not seen in controls
- DLK (MAP3K12)
: Loss of function
- jnk (MAPK8)
: Signaling requires DR6
- Inhibition: JNK kinase
; GSK3; IKKB (IKBKB)

- WD More rapid
- Galectin-3 loss
- Increased pro-inflammatory cytokines
- IL-1β, TNF-α, Toll-like receptor (TLR)-2 & -4
- Increased phagocytic capacity of Schwann cells & macrophages
- No effect: NGF
- WD: Molecular events
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- Early in axons
- Loss of m-Calpain
- Ca++ entry
- Associated cytokines
- Early: TNFα & 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
- Genetics
- Disorder: CONDCA
- Mutations (Animal): Purkinje cell degeneration (pcd) mouse
- Nerve injury associated kinase: Sensory neurons
- Molecules upregulated in nerve distal to transection
- Early activation of erbB2 4
- Related to: Schwann cell demyelination after axotomy
- 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
- Mimics 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)
- Molecules reduced in nerve distal to transection
- SCG10 (Stathmin-like 2; STMN2)
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- Reduced in distal stump before morphologic changes
- Promotes regeneration in proximal stump
- Heterozygous knockout: Motor axon damage
- Reduced in spinal cord in ALS
- Mice with slow Axon 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; May act in cytoplasm
- Expressed in: Skeletal muscle, Heart, Liver, Kidney & Brain
- Function: NAD biosynthesis
- Probably the component responsible for axonal protection
- NMNAT1 enzyme activity required for axon protection
- Sirt1
(NAD-dependent deacetylase)
- Downstream of NNMNAT
- Contributes to axonal protection
- E4B
- Subcellular location: Cytoplasmic
- Expressed in: Skeletal muscle, Ovary, Testis & Heart
- Functions
- Binds to ubiquitin moieties of conjugates
- Catalyzes ubiquitin chain assembly
- WldS mutation
- Chimeric gene product: 1st 70 AA Of Ube4b + NMNAT1 full sequence
- Causes ectopic localization of NMNAT1 (NAD+ biosynthesis enzyme) to axons
- May augment NMNAT2
- Maintains NMNAT enzyme activity in distal axons after injury
- Loss of NMNAT2
causes axon loss in vitro
- Site of action may be axonal ER/Golgi or mitochondria
- 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
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- Slightly longer survival
- Delayed denervation at NMJ
- Neuronal nitric oxide synthase knockout
2
- Slow Wallerian degeneration
- Delayed regeneration
- Incomplete pruning of axon sprouts: Enhanced number of axons
- Wallerian degeneration: Myelin changes
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- Early
- Anatomical: Widening of Schmidt-Lantermann incisura
- Ovoid formations begin at these loci
- Molecular
- Expression of Phospholipase A2 (Lipolytic enzyme)
- Activation of neuregulin-ErbB2 signaling (Demyelinating mechanisms)
- Actin polymerization
- E-cadherin recycling
- Paranodal myelin retraction
- Myelin "collapse" & fragmentation
- Myelin Degeneration
- Degenerative changes of myelin: Patterns
- Initial
- Within "Demyelinating" (Post-myelinating) Schwann cells
- Subcelllular: Begins along Schmidt-Lanterman clefts
- Associated with: c-Jun activation; Increased autophagic activity
- Anatomic along nerve: Distal to proximal direction
- Axon types: Small axons before Large axons
- Molecular markers of activity
- Mixed lineage kinase domain-like protein (MLKL)
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- Increased in Schwann cells & Macrophages
- Binds to sulfatide
- Final executioner of canonical necroptosis
- Induces loss of axon survival factors NMNAT2 & STMN2 to activate SARM1
- Myelin degradation associated with phosphorylation of MLKL serine 441
- MLKL knockout: Reduces or delays myelin breakdown & axon regeneration
- Myelin basic protein (MBP) still present in myelin fragments
- Consequence: Often signal, or attract, phagocytic macrophages
- Ovoid formation
- Primary ovoids: Early change (1 to 2 days)
- Intracellular (Schwann cell) myelin: Fragmentation
- Abaxonal Schwann cell cytoplasm
- Dilated
- Contains rough endoplasmic reticulum (RER) & vesicles
- Secondary ovoids (Myelinosomes): Later change (3 to 7 days)
- Pinched off from primary ovoid
- Compact myelin structures in Schwann cell cytoplasm
- Exocytosed from Schwann cell cytoplasm
- Into abaxonal extracellular space
- Myelin debris: May be further degraded by macrophages
- Macrophages
- ? Attracted by cytokines
- Phagocytosis & degradation of myelin debris
- Schwann cells
- Changes
- Proliferation: Especially non-myelinating Schwann cells
- De-differentiation: Myelinating Schwann cells
- Develop autophagic properties
- Degrade myelin sheath
- Auto-autophagy: Myelinating Schwann cells
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- Contain & Degrade: Myelin debris (Myelinophagy); MPZ & MBP proteins
- Autophagy markers increased: LC3-II; Wipi2
- Most prominent in 1st week after nerve injury
- Less autophagy by CNS oligodendroglia after axon damage
- Form Bands of Büngner
- Definition: Arrays of Schwann cells & processes within basement membrane
- Molecular: Büngner band Schwann cells express both NCAM & P0 protein
- Provide substrate for axonal regeneration
- Long-term: Schwannn cells atrophy and disappear if axonal regeneration does not occur
- Phagocytes (Macrophages): Degradation of myelin breakdown products to lipid debris
- Origin
- Mostly hematogenous incoming
- Recruitment regulated by: Raf–MEK–ERK mitogen-activated protein kinase
- Invasion of nerve 3 to 4 days after axon transection
- Phagocytosis of sudanophilic (lipid) debris: Appear as foamy cells
- Complement is necessary for phagocytosis
- Clear axonal & myelin debris
- 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
Alternate axon degeneration pathway: Trophic withdrawal induced
- Stimulus: Loss of trophic factors (NGF)
- Site of degeneration: Distal axon
- Pathway components
- Membrane related: p75; DR6
- Bax
- Caspases: 9; 6; 3
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Remak

Oppenheim 1894
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