Title: Chapter 7' Growth FACTORs Neurotrophic factors
1Chapter 7. Growth FACTORs - Neurotrophic
factors -
2Index
- 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
3Neurotrophic 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
4Nerve 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.
5Nerve 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.
6Nerve system (3)
7The 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
8The 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.
9The 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
10Neurotrophin 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.
11Neurotrophin 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
12Neurotrophin 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.
13Neurotrophin 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.
14Neurotrophin 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
15Neurotrophin receptors gt Summary
16Neurotrophin receptors gt Signaling
17Ciliary 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.
18Ciliary 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.
19Glial 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.
20CNTF and GDNF Summary
21Neurodegenerative 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.
22Neurodegenerative 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.
23Neurodegenerative 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
24Neurodegenerative 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.
25Neurodegenerative 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.
26Neurodegenerative 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.
27Neurodegenerative 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.
28Neurodegenerative disease gt Alzheimers disease
29Neurodegenerative 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 -
30Neurodegenerative 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.
31Combinatorial 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 !!!