Novel Neurotrophic Factors

Heparin – Binding Growth Factors

Heparin – binding growth factors have been implicated in central nervous system development, regeneration and pathology. Typical members of this family of secreted cytokines are basic Fibroblast Growth Factor (human FGF-basic), Midkine and Pleiotrophin.

human Midkine, a 13 kDa heparin-binding growth factor with 50% sequence identity to Pleiotrophin is the product of a retinoic acid responsive gene and is a developmental regulated, highly conserved, neurotrophic factor² which induces neurite extension^3,4 and neuronal survival⁵. human Pleiotrophin, an 18 kDa, heparin–binding growth – associated molecule (HB-GAM,HBGF-8)⁶ is also a developmentally regulated neurotrophin which promotes neurite out growth^7,8, axonal guidance⁹ and synaptogenesis⁶. Both factors are highly basic, lysine and cysteine rich which are produced in a recombinant form in E. coli¹⁰.

In vivo activities of these neurotrophic cytokines are cell surface and extracellular matrix-associated, promoting axonal growth, guidance, attachment and stabilization¹¹. Most probably these neurotrophic cytokines employ different cell-specific receptors which upon occupancy, activate multiple signal transduction pathways. Midkine and Pleiotrophin have been found to bind to the receptor protein-tyrosine phosphatase zeta (PTP zeta)¹², LDL receptor-related protein¹³, p200 (+) MKR cell surface receptor¹⁴, sulfatide¹⁵ and heparane-sulfate proteoglycans such as agrin¹⁶, N-syndecan⁹, ryudocan¹⁷ and neurocan¹². They stimulate tyrosine phosphorylation¹⁸, mitogen activated protein kinases (MAPKS), and phosphoinositide 3-kinase pathways⁵.

GDNF – Related Neurotrophin

human Persephin is a novel neurotrophic factor with 40% homology to human GDNF. Persephin, like GDNF, promotes the survival of mesencephalic dopaminergic and motor neurons in vitro^19,20. Recombinant Persephin is a homodimeric 20.6 kDa protein consisting of two identical, 96 amino acid subunits. Persephin binds with high affinity to GFRα putative family of receptors²¹ which induces RET phosphorylation²².