RT Journal Article
SR Electronic
T1 Intrastriatally Infused Exogenous CDNF Is Endocytosed and Retrogradely Transported to Substantia Nigra
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0128-16.2017
DO 10.1523/ENEURO.0128-16.2017
VO 4
IS 1
A1 Kert Mätlik
A1 Helena Vihinen
A1 Ali Bienemann
A1 Jaan Palgi
A1 Merja H. Voutilainen
A1 Sigrid Booms
A1 Maria Lindahl
A1 Eija Jokitalo
A1 Mart Saarma
A1 Henri J. Huttunen
A1 Mikko Airavaara
A1 Urmas Arumäe
YR 2017
UL http://www.eneuro.org/content/4/1/ENEURO.0128-16.2017.abstract
AB 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.