Chapter 7' Growth FACTORs Neurotrophic factors

1
Chapter 7. Growth FACTORs - Neurotrophic
factors -

• By Jaewon Jeon

2
Index

• Neurotrophic Factors
• Neurotrophins
• Neurotrophin receptors
• Neurotrophin low-affinity receptor
• Neurotrophic Factors and Neurodegenerative
  Disease
• Amyotrophic lateral sclerosis (ALS) and
  peripheral neuropathy
• Neurodegenerative diseases of the brain

3
Neurotrophic Factors

• a group of cytokines
• regulate the development, maintenance and
  survival of neurons
• in both the central and peripheral nervous
  systems
• Neurotrophins the major sub-family of
  neurotrophic factors
• specifically promote the growth and maintenance
  of those neurons

4
Nerve system (1)

• the central nervous system (CNS the brain and
  spinal cord)
• the peripheral nervous system (PNS additional
  neuronal elements).
• Sensory neurons leading from a
  stimulus-detecting receptor cell
• Motor neurons carry on nerve impulses to an
  effector cell (muscle cell)
• Neurons
• perikaryon - the nucleus-containing cell
  body
• dendrites - carry nerve impulses towards
  the perikaryon and the axon,
• synapse - the junction with the cell to
  which the nerve impulse will be transmitted.

5
Nerve system (2)

• The neuronal cytoskeleton
• - provides the axon with mechanical support
• - is directly involved in the transport of
  materials from the cell body towards the synapse
  (anterograde transport) and in the opposite
  direction (retrograde transport)
• Axons are generally covered (insulated) with a
  myelin sheath, which is formed by
  oligodendrocytes (in the CNS) or Schwann cells
  (PNS).
• After neurotrophic factor s release from the
  target cells,
• they bind specific receptors on the nerve
  termini, are internalized and carried up the axon
  to the perikaryon by retrograde transport.
• This process helps guide the direction of neurite
  growth (i.e. a chemoattractant activity) during
  neuronal development, and also serves to
  nourish the developing cell.

6
Nerve system (3)
7
The neurotrophins

• The neurotrophins are a group of neurotrophic
  factors which all belong to the same gene family.
  
• They include NGF, as well as brain-derived
  neurotrophic factor (BDNF), neurotrophin-3
  (NT-3), neurotrophin 4/5 (NT-4/5) and
  neurotrophin-6 (NT-6).
• All are small, basic proteins sharing
  approximately 50 amino acid homology.
• They exist mainly as homodimers and promote
  signal transduction by binding to a member of the
  Trk family

8
The neurotrophins gt NGF

• 120 aa, 26 kDa and pI 10
• three intra-chain disulphide linkages, which are
  essential for activity.
• synthesized and released from target tissues of
  sympathetic neurons and cholinergic basal
  forebrain neurons.
• also synthesized by non-neuronal tissue,
  including salivary glands, the prostate and mast
  cells.
• It functions to promote survival and stimulate
  growth of sensitive neurons, and accelerates
  neurotransmitter biosynthesis in most such cells.
  
• It also appears to stimulate growth and
  differentiation of B and T lymphocytes, thus
  potentially promoting cross-talk between the
  nervous and immune systems.

9
The neurotrophins gt BDNF, NT-3,-4/5,-6

• In contrast to NGF, BDNF is predominantly
  localized within the CNS.
• neurotrophin 3 (NT-3) expressed early inand
  throughoutembryogenesis.
• NT-4/5 originally cloned from Xenopus and
  mammals, respectively, turned out to be
  counterparts
• NT-6 has been discovered in the fish
  Xiphophorus.
• not released from the
  producing cell instead, it remains associated
  with the cell surface

10
Neurotrophin receptors

• Most neurotrophin-sensitive cells
• express two receptor types on their
  surface a high-affinity receptor, and a
  low-affinity receptor.
• Three Trks have been identified, Trk A, B and C.
• Ligand-binding
• ? homodimerization of Trk receptor
• ? activation of the intrinsic cytoplasmic
  tyrosine kinase activity
• ? receptor autophosphorylation and initiation of
  an intracellular response.

11
Neurotrophin receptors gt Trk A

• the high-affinity receptor for NGF (Kd10-11 M)
• expressed on the surface of sensory and
  sympathetic neurons, as well as the
  neuron-associated Schwann cells
• also expressed on the surface of mast cells,
  monocytes and lymphocytes
• a transmembrane glycoprotein, 140 kDa
• functions as a receptor for NT-3

12
Neurotrophin receptors gt Trk B

• receptor for BDNF and a functional receptor for
  NT-3 and NT-4/5
• Two variants of this glycoprotein have been
  characterized
• a larger (145 kDa) form and a truncated (95
  kDa) form
• expressed widely throughout the central and
  peripheral nervous system.

13
Neurotrophin receptors gt Trk C

• the functional receptor for NT-3.
• 145 kDa
• expressed by various neuronal cell populations,
  both in the brain and the PNS.

14
Neurotrophin receptors gt low-affinity receptor

• low-affinity receptor known as LNGFR, or P75.
• widely expressed, both on neuronal and
  non-neuronal cell populations
• p75s exact physiological role remains to be
  defined

15
Neurotrophin receptors gt Summary
16
Neurotrophin receptors gt Signaling
17
Ciliary neurotrophic factor (CNTF) and glial cell
line-derived neurotrophic factor (GDNF)

• CNTF and GDNF represent the most recently
  discovered members of the neurotrophic factor
  family.
• no homology to the neurotrophins previously
  discussed.

18
Ciliary neurotrophic factor (CNTF)

• originally characterized as a survival factor for
  chick ciliary neurons
• 200 aa (22 kDa) polypeptide.
• The CNTF receptor
• unusual? not a transmembrane protein,
  but is anchored to the membrane by a
  glycosyl-phosphatidylinositol linkage.
• unrelated to the Trk family of
  neurotrophin receptors but displays homology with
  the IL-6 receptor.
• Ligand-binding appears to induce CNTF interaction
  with additional membrane proteins, notably the
  LIF receptor and gp130
• ? phosphorylation of these latter two
  molecules.

19
Glial cell line-derived neurotrophic factor (GDNF)

• 34kDa homodimeric glycosylated protein
• a member of the TGF-b family
• influences a wide range of neuronal populations,
  including spinal sensory and motor neurons
• also stimulates dopaminergic neurons
• the most potent survival factor for motor neurons
  in vitro.

20
CNTF and GDNF Summary
21
Neurodegenerative disease

• generally characterized by the death of specific
  neuronal populations.
• Target diseases include
• amyotrophic lateral sclerosis(ALS) and
  peripheral neuropathies, as well as various
  neurodegenerative diseases of the brain,
  including Alzheimers and Parkinsons.

22
Neurodegenerative disease gt Amyotrophic lateral
sclerosis (ALS)

• degeneration of the spinal and brainstem motor
  neurons
• 70 000 people worldwide.
• Pre-clinical trials (as well as phase I and II
  clinical trials) utilizing CNTF yielded promising
  results
• ? but the neurotrophic factor then failed
  in phase III clinical trials (insufficient
  efficacy)
• However, myotrophin (IGF-1) has proved more
  successful.

23
Neurodegenerative disease gt Amyotrophic lateral
sclerosis (ALS)
ALS is also known as Lou Gehrig's disease, after
the famous baseball player who died of the
disease in 1941
Renowned scientist Stephen Hawking suffers from
ALS
24
Neurodegenerative disease gt peripheral neuropathy

• degeneration of peripheral sensory and/or motor
  neurons
• It often occurs as a complication of diabetes or
  in cancer patients receiving chemotherapy.
• Pre-clinical studies
• ?NGF, along with IGF-1, can prevent the
  occurrence of drug-induced peripheral neuropathy
  in animals. Human clinical trials continue.

25
Neurodegenerative disease gt peripheral neuropathy

Peripheral neuropathy is a disorder characterized
by damage to the nerves that transmit sensation
to the central nervous system, which consists of
the spinal cord and the brain. The peripheral
nerves that are affected first are generally in
the hands and feet. Unfortunately, the problem
can be progressive and can lead to foot ulcers,
amputation and death.
26
Neurodegenerative disease gt Alzheimers and
Parkinsons

• the death of CNS neurons
• bloodbrain barrier (BBB) preclude delivery of
  the drug to the brain via IV injection.
• Problem solving, including
• 1 direct injection of neurotrophic
  factor into the brain
• 2 use of cranial infusion pumps
• 3 intraventricular transplantation of
  recombinant polymer-encapsulated cells which
  secrete neurotrophic factors.
• Alternative approach
• conjugating the neurotrophic factor to
  monoclonal antibodies raised against the
  transferrin receptor.
• ex NGFanti-transferrin antibody
  conjugate ? translocation across the bloodbrain
  barrier.

27
Neurodegenerative disease gt Alzheimers disease

• Loss of cholinergic neurons of the basal
  forebrain
• NGF can rescue such cells in rodents after damage
  induced by cutting their axons.
• Infusion of NGF and NT-4/5 to aged rats improve
  their spatial memory ability.
• physical exercise increased BDNF expression,
  which may explain why exercise is often a
  predictor of high mental function during ageing.

28
Neurodegenerative disease gt Alzheimers disease
29
Neurodegenerative disease gt Parkinsons disease

• Degeneration of dopaminergic neurons of the
  substantia nigra
• Several neurotrophic factors, including NT-4/5,
  BDNF and GDNF may be useful
• Pre-clinical studies
• direct injection of GDNF prevents
  degeneration of damaged neurons

30
Neurodegenerative disease gt Parkinsons disease
The boxer Muhammad Ali and the actor Michael J.
Fox suffer from Parkinson's disease. Both have
supported efforts to find a cure.
31
Combinatorial Theraphy

• The use of a combination of neurotrophic factors
  in the treatment of neurodegenerative disease
• pre-clinical studies
• a combination of CNTF and BDNF to Wobbler
  mice (an animal model of motor neuron disease) ?
  prevented progression of motor neuron dysfuction

32

• Thank you for your attention !!!