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Chapter 7' Growth FACTORs Neurotrophic factors

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Title: 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 !!!
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