Myelin structure, formation, and related diseases

Nervous System

Functions

• Recepetion of information
• integration and analysis of the incoming information
• generation of new signals
• conduction of these neural messages to special response tissue (effectors)

Divisions

• Central Nervous System (CNS)
  • Brain
  • Spinal cord
• Peripheral Nervous System (PNS)
  • All nerves and other parts outside the CNS
  • consists of 12 pairs of cranial nerves and 31 pairs of spinal nerves

Neuronal structure

• Cell body - nucleus, cytoplasm, organelles
• Dendrites - highly branched, receive signals
• Axon - conducts away from cell body toward another neuron, muscle, or gland
• Axon terminals - contain synaptic vesicles that can release neurotransmitters

Neuroglia for myelination

• Oligodendrocyte
• Schwann cell
• Astrocyte

Structure of myelinated axons

Conduction of nerve impulses

Arrows show the flow of action currents in local circuits into the active region of the membrane

• unmyelinated
  
  The circuits flow throught the adjacaent piece of membrane
• myelinated
  
  The circuit flow jumps to the next node

Continuous conduction (unmyelinated fibers)

Step by step depolarization along the entire length of the axon

Saltatory conduction (myelinated fibers)

* Depolarization only at the nodes of Ranvier * Current flows through the extracellular fluid from node to node

Myelin (~70% lipid, 30% protein)

Biosynthesis of glycosphinogolipids

Ceramide, the precursor for galactolipids, gangliosides, and sphingomyelin

• oligodendrocytes in the CNS
• broad, flat cell processes that wrap around axons, but cell bodies do not surround the axons
• no neurilemma is formed
• little regrowth after injury is possible due to the lack of a distinct tube or neurilemma

Myelination in CNS

The whole myelin internode forms a spade-shaped sheet surrounded by a cotinuous tube of oligodendroglial cell cytoplasm

Myelination in PNS

Myelin formation in the peripheral nervous system

1. Schwann cell surrounds the axon but the external surfaces of the plasma membrane have not yet fused in the mesaxon
2. The mesaon has fused into a five-layered structure and spiraled once around the axon
3. A few layers of myelin have formed but are not yet compacted
4. Compact myelin showing only a few layers for the sake of clarity

Myelinated and unmyelinated axons in PNS

Multiple Sclerosis (MS)

Classification

• Progressive Relapsing MS (PRMS)
  Steady decline since onset with super-imposed attacks
• Secondary Progressive MS (SPMS)
  Initial RRMS that suddenly begins to decline without periods of remission and relapse
• Primary Progressive MS (PPMS)
  Gradual progression of the disease from its onset with no relapses or remissions
• Relapsing/Remitting MS (RRMS) (80~85%)
  Unpredictable attacks that may or may not leave permanent deficits followed by periods of remission

Pathogenesis of multiple sclerosis

Diagnosis

• Expanded Disability Status Scale (EDSS)
  a method of quantifying disability in multiple sclerosis based on eight functional systems (FS)
  • Pyramidal (ability to walk)
  • Cerebellar (coordination)
  • Brainstem (speech, swallowing)
  • Sensory (touch, pain)
  • Bowel and bladder
  • Visual
  • Mental
  • Other (any other neurological findings)
• Cerebrospinal fluid (CSF) analysis
  • oligoclonal bands
  • elevated IgG index
  • abnormal colloidal gold curve
  • mild mononuclear pleocytosis
  • myelin debris
  • normal or slightly elevated protein
• Blood tests
• MRI

Treatment

• Two generally accepted strategies
  • peventing CNS damage indirectly through immunomodulatory interventions (by reducing inflammation that causes axon damage in the acute and possibly chronic lesion)
  • repairing the CNS damage by promoting remyelination (by restoring functionality of the myelin sheath on which axonal health depends)

Axon regeneration in CNS and PNS

Classification of nerve injury

Severed axons in the PNS can regenerate but severed axons in the CNS cannot

What happens to the cell body?

• Chromatolysis
  • Nissl substance or RER dissolute and decrease in cytoplasmatic basophilia
  • Nucleus assumes an eccentric position and the whole body swells
  • The closer the injury is to the body the more severe the swelling
• Transneuronal degeneration
  • Occurs in neuronal bodies that have been deprived of their input or output
  • This can be either anterograde or retrograde

Neuronal responses to axotomy

Trans-neural degeneration

Various forms of axonal degeneration

Wallerian axon degeneration

Neuronal injury in CNS and PNS

Formation of a retraction bulb and its rescue

Glial inhibitors and intracellular signaling mechanisms (CNS)

Degeneration and regeneration after peripheral nerve injury (PNS)

1. Normal nerve fiber, maintaining synaptic contact with target cells
2. Wallerian degeneration
3. Schwann cells in the distal segment line up in bands of burgner
   Axonal sprouts advance embedded in the Schwann cell and attracted by gradients of neurotrophic factors
4. Axonal reconnection with end organs and maturation and remyelination of the nerve fiber
   

Difficulties in CNS regeneration

1. Dense glia scar in the injured part
2. Axon disables to penetrate the densed glia scar
3. No effective clearance of the debris around the injured axon by macrophage (BBB)
4. No band of burgner (no de-differentiation of Schwann cells)

Glial Scar

• Regeneration strategies
  Cellular replacement

Neural regeneration in CNS

• Regeneration strategies
  Neurotrophic factor delivery

Cocktail of neurotrophic factors combination

1. GDNF (Glial cell line-derived neurotrophic factor)
2. BDNF (Brain-derived neurotrophic factor)
3. NT-3 (Neurotrophin-3)
4. BDNF (Brain-derived neurotrophic factor)
5. NGF (Nerve growth factor)

inject into the Nerve conduits

• Regeneration strategies
  Manipulation of intracellular signaling

Intracellular mediators of axon growth

• Regeneration strategies
  Axon guidance and removal of growth
  Modulation of the immune response