title: Intrastriatally Infused Exogenous CDNF Is Endocytosed and Retrogradely Transported to Substantia Nigra.
abstract: Cerebral dopamine neurotrophic factor (CDNF) protects the nigrostriatal dopaminergic (DA) neurons in rodent models of Parkinson's disease and restores DA circuitry when delivered after these neurons have begun to degenerate. These DA neurons have been suggested to transport striatal CDNF retrogradely to the substantia nigra (SN). However, in cultured cells the binding and internalization of extracellular CDNF has not been reported. The first aim of this study was to examine the cellular localization and pharmacokinetic properties of recombinant human CDNF (rhCDNF) protein after its infusion into rat brain parenchyma. Second, we aimed to study whether the transport of rhCDNF from the striatum to the SN results from its retrograde transport via DA neurons or from its anterograde transport via striatal GABAergic projection neurons. We show that after intrastriatal infusion, rhCDNF diffuses rapidly and broadly, and is cleared with a half-life of 5.5 h. Confocal microscopy analysis of brain sections at 2 and 6 h after infusion of rhCDNF revealed its widespread unspecific internalization by cortical and striatal neurons, exhibiting different patterns of subcellular rhCDNF distribution. Electron microscopy analysis showed that rhCDNF is present inside the endosomes and multivesicular bodies. In addition, we present data that after intrastriatal infusion the rhCDNF found in the SN is almost exclusively localized to the DA neurons, thus showing that it is retrogradely transported.
authors.affiliation: Program in Developmental Biology, Institute of Biotechnology, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Kert
authors.initials: K
authors.lastname: Mätlik
authors.affiliation: Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Vihinen
authors.affiliation: Functional Neurosurgery Research Group, Learning and Research Building, School of Clinical Sciences, Southmead Hospital, University of Bristol , Bristol BS10 5NB, United Kingdom.
authors.forename: Ali
authors.initials: A
authors.lastname: Bienemann
authors.affiliation: Department of Gene Technology, Tallinn University of Technology , 12618 Tallinn, Estonia.
authors.forename: Jaan
authors.initials: J
authors.lastname: Palgi
authors.affiliation: Program in Developmental Biology, Institute of Biotechnology, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Merja H
authors.initials: MH
authors.lastname: Voutilainen
authors.affiliation: Herantis Pharma Plc , 00790 Helsinki, Finland.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Booms
authors.affiliation: Program in Developmental Biology, Institute of Biotechnology, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Maria
authors.identifier: 0000-0002-5674-8830
authors.initials: M
authors.lastname: Lindahl
authors.affiliation: Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Eija
authors.identifier: 0000-0002-4159-6934
authors.initials: E
authors.lastname: Jokitalo
authors.affiliation: Program in Developmental Biology, Institute of Biotechnology, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Mart
authors.identifier: 0000-0001-5543-7160
authors.initials: M
authors.lastname: Saarma
authors.affiliation: Herantis Pharma Plc, 00790 Helsinki, Finland; Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Henri J
authors.identifier: 0000-0002-9867-4438
authors.initials: HJ
authors.lastname: Huttunen
authors.affiliation: Program in Developmental Biology, Institute of Biotechnology, University of Helsinki , 00014 Helsinki, Finland.
authors.forename: Mikko
authors.identifier: 0000-0002-2026-1609
authors.initials: M
authors.lastname: Airavaara
authors.affiliation: Program in Developmental Biology, Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland; Department of Gene Technology, Tallinn University of Technology, 12618 Tallinn, Estonia.
authors.forename: Urmas
authors.initials: U
authors.lastname: Arumäe
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000648:ultrastructure; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D016253:Microscopy, Immunoelectron; D009414:Nerve Growth Factors / Q000008:administration & dosage* / Q000378:metabolism / Q000648:ultrastructure; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; C522217:CDNF protein, human; D009414:Nerve Growth Factors; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase
keywords: CDNF; Parkinson’s disease