title: Developing therapeutically more efficient Neurturin variants for treatment of Parkinson's disease.
abstract: In Parkinson's disease midbrain dopaminergic neurons degenerate and die. Oral medications and deep brain stimulation can relieve the initial symptoms, but the disease continues to progress. Growth factors that might support the survival, enhance the activity, or even regenerate degenerating dopamine neurons have been tried with mixed results in patients. As growth factors do not pass the blood-brain barrier, they have to be delivered intracranially. Therefore their efficient diffusion in brain tissue is of crucial importance. To improve the diffusion of the growth factor neurturin (NRTN), we modified its capacity to attach to heparan sulfates in the extracellular matrix. We present four new, biologically fully active variants with reduced heparin binding. Two of these variants are more stable than WT NRTN in vitro and diffuse better in rat brains. We also show that one of the NRTN variants diffuses better than its close homolog GDNF in monkey brains. The variant with the highest stability and widest diffusion regenerates dopamine fibers and improves the conditions of rats in a 6-hydroxydopamine model of Parkinson's disease more potently than GDNF, which previously showed modest efficacy in clinical trials. The new NRTN variants may help solve the major problem of inadequate distribution of NRTN in human brain tissue.
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland. Electronic address: pia.runeberg@helsinki.fi.
authors.forename: Pia
authors.initials: P
authors.lastname: Runeberg-Roos
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Piccinini
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Anna-Maija
authors.initials: AM
authors.lastname: Penttinen
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Kert
authors.initials: K
authors.lastname: Mätlik
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Heikkinen
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Kuure
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Maxim M
authors.initials: MM
authors.lastname: Bespalov
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Peränen
authors.affiliation: Department of Neuroanatomy, Institute for Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Enrique
authors.initials: E
authors.lastname: Garea-Rodríguez
authors.affiliation: German Primate Center, Göttingen, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Fuchs
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Airavaara
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Nisse
authors.initials: N
authors.lastname: Kalkkinen
authors.affiliation: CNS Therapeutics Inc., 332 Minnesota Street, Ste W1750, St. Paul, MN 55101, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Penn
authors.affiliation: Institute of Biotechnology, University of Helsinki, PB 56 (Viikinkaari 5D), FIN-00014, Finland.
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D015195:Drug Design; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D051101:Neurturin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects; D013565:Sympatholytics / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D051101:Neurturin; D013565:Sympatholytics; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: GDNF; GFRα1; GFRα2; Growth factor; Heparan sulfate; Heparin; NRTN; Neurturin; Parkinson's disease; RET