Transforming growth factor beta1 overexpression in the nigrostriatal system increases the dopaminergic deficit of MPTP mice.
Idiopathic Parkinson's disease (PD) is characterized by mesencephalic dopaminergic neuron cell death and striatal dopamine (DA) depletion. The factors involved in the pathogenesis of the disease are still unknown. Transforming growth factor beta1 (TGFbeta1) is increased in the striatum of patients with PD. However, the effect of this increase is not known. Here, we show that overexpression of TGFbeta1, by recombinant adenovirus TGFbeta1 gene transfer, in the mesostriatal system of an MPTP mouse model of PD decreased the number of mesencephalic dopaminergic neurons. This effect also involved more extensive DA depletion in the striatum. Striatal enkephalin mRNA levels are augmented, suggesting a decrease in dopaminergic transmission to the postsynaptic target. In the absence of MPTP, TGFbeta1 greatly decreased the number of dopaminergic neurons in the ventral mesencephalon of fully mature mice. These results show that an increase in TGFbeta1 levels aggravate the parkinsonian status of MPTP mice and may therefore be a risk factor for the development of PD.
Sánchez-Capelo
Amelia
A
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, CNRS UMR7091, Bât. CERVI, Hôpital de la Pitié, Salpêtrière, 83, Bd. de I'Hôpital, 75013 Paris, France. amelia.capelo@hrc.es
Colin
Philippe
P
Guibert
Bernard
B
Biguet
Nicole Faucon
NF
Mallet
Jacques
J
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency*; D015536:Down-Regulation / Q000235:genetics; D004745:Enkephalins / Q000235:genetics; D018014:Gene Transfer Techniques; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000378:metabolism* / Q000503:physiopathology; D009434:Neural Pathways / Q000378:metabolism* / Q000503:physiopathology; D020734:Parkinsonian Disorders; D012333:RNA, Messenger / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics
D004745:Enkephalins; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004298:Dopamine