TY - JOUR T1 - Intra-striatally infused exogenous CDNF is endocytosed and retrogradely transported to substantia nigra JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0128-16.2017 SP - ENEURO.0128-16.2017 AU - Kert Mätlik AU - Helena Vihinen AU - Ali Bienemann AU - Jaan Palgi AU - Merja H. Voutilainen AU - Sigrid Booms AU - Maria Lindahl AU - Eija Jokitalo AU - Mart Saarma AU - Henri J. Huttunen AU - Mikko Airavaara AU - Urmas Arumäe Y1 - 2017/02/13 UR - http://www.eneuro.org/content/early/2017/02/13/ENEURO.0128-16.2017.abstract N2 - 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 5.5h. Confocal microscopy analysis of brain sections at 2h and 6h 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.Significance Statement The wide spreading and unspecific uptake of rhCDNF after its delivery into brain parenchyma imply that therapeutically applied CDNF could directly influence a large number of cells in different brain areas. In addition, we show that infused rhCDNF is retrogradely transported from the striatum to the substantia nigra by the dopamine neurons that it rescues in rodent models of Parkinson’s disease. Along with the presented pharmacokinetic characteristics of rhCDNF after intrastriatal delivery, this information on the distribution of infused rhCDNF is important for the design of subsequent preclinical and clinical trials. ER -