title: Persephin signaling through GFRalpha1: the potential for the treatment of Parkinson's disease.
abstract: Neurotrophic factors promote survival, proliferation and differentiation of neurons inducing intracellular signaling via specific receptors. The conventional biochemical methods often fail to reveal full repertoire of neurotrophic factor-receptor interactions because of their limited sensitivity. We evaluated several approaches to study signaling of Glial cell line-Derived Neurotrophic Factor (GDNF) family ligands and found that reporter-gene systems possess exceptionally high sensitivity and a heuristic power to identify novel biologically relevant growth factor-receptor interactions. We identified persephin, a GDNF family member, as a novel ligand for GFRalpha1/RET receptor complex. We confirmed this finding by several independent methods, including neurite outgrowth assay from the explants of sympathetic ganglia expressing Gfralpha1 and Ret mRNA but not persephin's conventional receptor GFRalpha4. As the activation of GFRalpha1/RET was shown to rescue dopaminergic neurons, our results suggest the potential of persephin for the treatment of Parkinson's disease.
authors.affiliation: Institute of Biotechnology, Viikki Biocenter, University of Helsinki, Helsinki, FIN-00014, Finland.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Sidorova
authors.forename: Kert
authors.initials: K
authors.lastname: Mätlik
authors.forename: Mikhail
authors.initials: M
authors.lastname: Paveliev
authors.forename: Maria
authors.initials: M
authors.lastname: Lindahl
authors.forename: Elisa
authors.initials: E
authors.lastname: Piranen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
authors.forename: Urmas
authors.initials: U
authors.lastname: Arumäe
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
authors.forename: Maxim M
authors.initials: MM
authors.lastname: Bespalov
mesh_terms: D000818:Animals; D001681:Biological Assay / Q000379:methods; D002460:Cell Line; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009414:Nerve Growth Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D010300:Parkinson Disease / Q000628:therapy*; D011487:Protein Conformation; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C110758:persephin; D051096:Proto-Oncogene Proteins c-ret