Neurotrophic Factor Families

The designation of five cytokine families based upon receptor structural homology is rather vague. Cytokines within each structural family have further diversity in function hence. 

The neurotrophin family includes NGF, BDNF, neurotrophin-3 (NT-3), NT-4/5, and NT-6. All neurotrophins are capable of binding to the p75 receptor each neurotrophin also binds to a specific Trk receptor. Trk is the receptor for NGF TrkB is the receptor for BDNF and NT-4, while TrkC is the receptor for NT-3. Neurotrophins secreted by cells protect neurons from apoptosis (Korsching, 1993 Lewin and Barde, 1996). Similarly, ciliary neurotrophic factor (CNTF), a structurally related type I cytokine and GDNF, structurally related to TGF-[3, each constitute a sub-family of neurotrophic factors. 

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The glial-derived neurotrophic factor family represents a newly recognized family of target-derived neurotrophic factors 480... 

Ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) represent the most recently discovered members of the neurotrophic factor family. These, however, display no homology to the neurotrophins previously discussed. 

Malin SA, Molliver DC, Koerber HR, Comuet P, Frye R, Albers KM, Davis BM (2(X)6) Glial cell hne-deiived neurotrophic factor family members sensitize nociceptors in vitro and produce thermal hyperalgesia in vivo. J Neurosci 26 8588-8599 Malkmus S, Lu X, Bartfai T, Yaksh TL, Hua XY (2005) Increased hyperalgesia after tissue injury and faster recovery of allodynia after nerve injury in the GalRl knockout mice. Neuropeptides 39 217-221... 

Hohn, A., Leibrock, J., Bailey, K. and Barde, Y.A. (1990) Identification and characterization of a novel member of the nerve growth factor/brain derived neurotrophic factor family. Nature 344 339-341. 

Neurotrophins (NGF brain-derived neurotrophic factor, BDNF neurotrophin-3, NT-3 NT-4 NT-6) are important regulators of neural survival, development, function, and plasticity of the vertebrate nervous system [1]. Neurotrophins generally function as noncovalently associated homodimers. They activate two different classes of receptors, through which signaling pathways can be activated, including those mediated by Ras and members of the cdc42/rac/rho G protein families, MAP kinase, PI-3 kinase, and Jun kinase cascades. 

Neurotrophic factors constitute a group of cytokines that regulate the development, maintenance and survival of neurons, both in the central and peripheral nervous systems (Table 10.12). Although the first member of this family (NGF) was discovered more than 50 years ago, it is only in the last decade that the other members have been identified and characterized. The major subfamily of neurotrophic factors is the neurotrophins. 

Neuronal survival and differentiation are regulated by many factors including neurotrophins and the Trk family of RPTKs. The prototype neurotrophin, nerve growth factor (NGF), promotes the survival of neurons during a period of programmed cell death in embryonic and early postnatal developmental stages. It is a target-derived neurotrophic factor that modulates the functions of the... 

The neurotrophins comprise a family of highly related molecules that act to support the survival and phenotypic specificity of select subsets of neurons. The neurotrophins (Table 27-2) are small highly basic proteins of approximately 13kDa that dimerize to form the biologically active species [5]. The neurotrophins have a highly conserved structure. This family includes five distinct members NGF,brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), neurotrophin 4/5 (NT4/5) and neurotrophin 6 (NT6). NT6 is found only in fish and will not be discussed further. 

FIGURE 2 7-2 Neurotrophin receptors. Neurotrophin family members bind specifically to cognate Trk receptors. The low affinity neurotrophin receptor, p75, promiscuously binds all neurotrophins. BDNF, brain-derived neurotrophic factor NGF, nerve growth factor NT, neurotrophin. 

CNTF ciliary neurotrophic factor fCJD familial Creutzfeldt-Jakob disease... 

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 of tyrosine kinase receptors (Table 7.10). 

Table 7.10. Biochemical characteristic of the neurotrophin family of neurotrophic factors. Except for NT-6, the molecular masses quoted are those of the homodimeric structure, which represents their biologically active forms. See text for further details...

Limited clinical success keeps optimism alive that neurotrophic factors will find application in the treatment of some neurodegenerative disease. However, no member of this family of regulatory proteins have been approved for medical use, despite all the clinical investigations undertaken over the last decade and a half... 

Neurotropic factors of dopaminergic neurons may represent a potential neuroprotective therapy for Parkinson s disease. Apart from nerve growth factor (NGF), the family of the neurotrophins subsumes at the present time BDNF, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). However, the concept of neurotrophic factors as specific, target-derived molecules, each acting on distinct neuronal types, has to be modified because of their high degree of pleiotropism and a... 

The neurotrophins represent a family of survival and differentiation factors that exert profound effects in the central and peripheral nervous systems. The neurotrophins are currently under investigation as therapeutic agents for the treatment of neurodegenerative disorders and nerve injury either individually or in combination with other trophic factors such as ciliary neurotrophic factor (CNTF) or fibroblast growth factor (FGF). 

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