GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function

• DOI: 10.1371/journal.pgen.1005710
• Publication Date: 2015-12-17T19:18:57Z
• Authors: Anmol Kumar; Jaakko Kopra; Kärt Varendi; Lauriina L. Porok...; Anne Panhelainen; Satu Kuure; Pepin Marshall; Nina Karalija; Mari-Anne Härma; Carolina Vilenius; Kersti Lilleväli; Triin Tekko; Jelena Mijatovic; Nita Pulkkinen; Madis Jakobson; Maili Jakobson; Roxana Ola; Erik Palm; Maria Lindahl; Ingrid Strömberg; Vootele Võikar; T. Petteri Piepponen; Mart Saarma; Jaan-Olle Andressoo
• Keywords: Central Nervous System; Dopamine; Dopaminergic Neurons; Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy); Gene Expression Regulation, Developmental; QH426-470; Kidney; Acetylcysteine; 3. Good health; Neostriatum; Substantia Nigra; Biomedicine; Disease Models, Animal; Mice; Neuroprotective Agents; Genetics, developmental biology, physiology; Genetics; Animals; Humans; Glial Cell Line-Derived Neurotrophic Factor; Parkinson Disease, Secondary; Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Research Article

Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival dopamine neurons vitro and vivo, intracranial delivery GDNF has been attempted for disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role endogenous at sites its expression important. However, due to limitations existing genetic model systems, such scarce. Here, we report that prevention transcription Gdnf 3'UTR locus yields hypermorphic mice increased, spatially unchanged expression, enabling analysis postnatal function. We found increased level central nervous increases number adult substantia nigra pars compacta terminals dorsal striatum. At functional level, levels striatal tissue augmented release re-uptake. In a proteasome inhibitor lactacystin-induced were protected from reduction failure Importantly, adverse phenotypic effects associated unregulated applications not observed. Enhanced up-regulated transporter activity by least five fold resulting enhanced susceptibility 6-OHDA, toxin transported into DAT. Further, how regulate kidney development identify microRNAs miR-9, miR-96, miR-133, miR-146a as negative regulators via interaction vitro. Our results reveal function, highlight importance correct spatial GDNF. Furthermore, our suggest targeting may constitute useful tool analyzing gene