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GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function.
Kumar, Anmol; Kopra, Jaakko; Varendi, Kärt; Porokuokka, Lauriina L; Panhelainen, Anne; Kuure, Satu; Marshall, Pepin; Karalija, Nina; Härma, Mari-Anne; Vilenius, Carolina; Lilleväli, Kersti; Tekko, Triin; Mijatovic, Jelena; Pulkkinen, Nita; Jakobson, Madis; Jakobson, Maili; Ola, Roxana; Palm, Erik; Lindahl, Maria; Strömberg, Ingrid; Võikar, Vootele; Piepponen, T Petteri; Saarma, Mart; Andressoo, Jaan-Olle.
Afiliación
  • Kumar A; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Kopra J; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
  • Varendi K; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Porokuokka LL; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Panhelainen A; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Kuure S; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Marshall P; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Karalija N; Department of Histology and Cell Biology, Umeå University, Umeå, Sweden.
  • Härma MA; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Vilenius C; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Lilleväli K; Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
  • Tekko T; Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
  • Mijatovic J; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
  • Pulkkinen N; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
  • Jakobson M; Department of Biochemistry and Developmental Biology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
  • Jakobson M; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Ola R; Department of Biochemistry and Developmental Biology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
  • Palm E; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Lindahl M; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Strömberg I; Department of Histology and Cell Biology, Umeå University, Umeå, Sweden.
  • Võikar V; Neuroscience Center and Department of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
  • Piepponen TP; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
  • Saarma M; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • Andressoo JO; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
PLoS Genet ; 11(12): e1005710, 2015 Dec.
Article en En | MEDLINE | ID: mdl-26681446
Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson's disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3'UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson's disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3'UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct spatial expression of GDNF. Furthermore, our results suggest that 3'UTR targeting may constitute a useful tool in analyzing gene function.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de Parkinson Secundaria / Sustancia Negra / Dopamina / Factor Neurotrófico Derivado de la Línea Celular Glial / Neuronas Dopaminérgicas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2015 Tipo del documento: Article País de afiliación: Finlandia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de Parkinson Secundaria / Sustancia Negra / Dopamina / Factor Neurotrófico Derivado de la Línea Celular Glial / Neuronas Dopaminérgicas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: PLoS Genet Asunto de la revista: GENETICA Año: 2015 Tipo del documento: Article País de afiliación: Finlandia