RT Journal Article
T1 Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons
A1 Enterría-Morales, Daniel
A1 López-González del Rey, Natalia
A1 Blesa, Javier
A1 López-López, Ivette
A1 Gallet, Sarah
A1 Prévot, Vincent
A1 López-Barneo, José
A1 d'Anglemont de Tassigny, Xavier
K1 Parkinson’s disease
K1 Pro-endo-GDNF pharmacology
K1 Parvalbumin interneurons
K1 Striatum
K1 Gene expression
K1 Enfermedad de Parkinson
K1 Factor neurotrófico derivado de la línea celular glial
K1 Parvalbúminas
K1 Cuerpo estriado
K1 Expresión Génica
AB Administration of recombinant glial cell line-derived neurotrophic factor into the putamen has been tested in preclinical and clinical studies to evaluate its neuroprotective effects on the progressive dopaminergic neuronal degeneration that characterizes Parkinson's disease. However, intracerebral glial cell line-derived neurotrophic factor infusion is a challenging therapeutic strategy, with numerous potential technical and medical limitations. Most of these limitations could be avoided if the production of endogenous glial cell line-derived neurotrophic factor could be increased. Glial cell line-derived neurotrophic factor is naturally produced in the striatum from where it exerts a trophic action on the nigrostriatal dopaminergic pathway. Most of striatal glial cell line-derived neurotrophic factor is synthesized by a subset of GABAergic interneurons characterized by the expression of parvalbumin. We sought to identify molecular targets specific to those neurons and which are putatively associated with glial cell line-derived neurotrophic factor synthesis. To this end, the transcriptomic differences between glial cell line-derived neurotrophic factor-positive parvalbumin neurons in the striatum and parvalbumin neurons located in the nearby cortex, which do not express glial cell line-derived neurotrophic factor, were analysed. Using mouse reporter models, we have defined the genomic signature of striatal parvalbumin interneurons obtained by fluorescence-activated cell sorting followed by microarray comparison. Short-listed genes were validated by additional histological and molecular analyses. These genes code for membrane receptors (Kit, Gpr83, Tacr1, Tacr3, Mc3r), cytosolic proteins (Pde3a, Crabp1, Rarres2, Moxd1) and a transcription factor (Lhx8). We also found the proto-oncogene cKit to be highly specific of parvalbumin interneurons in the non-human primate striatum, thus highlighting a conserved expression between species and suggesting that specific genes identified in mouse parvalbumin neurons could be putative targets in the human brain. Pharmacological stimulation of four G-protein-coupled receptors enriched in the striatal parvalbumin interneurons inhibited Gdnf expression presumably by decreasing cyclic adenosine monophosphate formation. Additional experiments with pharmacological modulators of adenylyl cyclase and protein kinase A indicated that this pathway is a relevant intracellular route to induce Gdnf gene activation. This preclinical study is an important step in the ongoing development of a specific pro-endo-glial cell line-derived neurotrophic factor pharmacological strategy to treat Parkinson's disease.
PB Oxford University Press on behalf of the Guarantors of Brain
YR 2020
FD 2020-07-15
LK http://hdl.handle.net/10668/3776
UL http://hdl.handle.net/10668/3776
LA en
NO Enterría-Morales D, López-González del Rey N, Blesa J, López-López I, Gallet S, Prévot V, et al. Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons. Brain Commun. 2020 Aug 27;2(2):fcaa105
DS RISalud
RD Apr 11, 2025