Novel transcriptional regulation mechanisms associated with Parkinson’s disease pathogenesis: from biological activity towards therapy

• Autor(a) principal: Nunes, Jéssica Lopes
• Data de Publicação: 2017
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.6/6686
• topic: 6-Ohda; Doença de Parkinson; Mtob; Proteínas de Ligação C-Terminal; Sobrevivência Dopaminérgica; Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas

There is growing evidence of an important role of epigenetic on the progression of neurodegenerative diseases, like Parkinson’s disease (PD). C-terminal binding proteins (CtBPs) are transcriptional co-repressors that exert transcriptional repression primarily via recruitment of a co-repressor complex to DNA. Some studies have demonstrated a critical function for CtBP1 and CtBP2 in the transcriptional repression of pro-apoptotic genes, suggesting being good therapeutic target for neurodegenerative diseases. Herein, we explored the expression of CtBPs in in vitro and in vivo models for PD by western-blotting, and their putative effect on dopaminergic survival by the MTT assay (in vitro) or by tyrosine hydroxylase cell countings (in vivo). First, increased expression of CtBP1 was found in the substantia nigra (SN) of 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) challenged mice, while a significant increased expression was found in the striatum (ST) of mice challenged with 6-OHDA only. CtBP2 expression was increased both in the SN and ST of 6-OHDA treated mice, although not reaching statistical significance when compared with saline mice. In accordance, the expression of both CtBP1 and CtBP2 was increased in a rat dopaminergic neural cell line (N27) exposed to 6-OHDA. Then, a broad antagonist of CtBPs, the 4-methylthio 2-oxobutyric acid (MTOB), was used to assess the putative role of CtBPs on neuronal survival. MTOB, at relatively high concentrations, was able to inhibit dopaminergic survival in N27 cells and in the SN of 6-OHDA in vivo mouse model for PD. Moreover, MTOB was able to potentiate cell death induced by 1-methyl-4-phenylpyridinium (MPP+). Interestingly, low doses of MTOB (250 µM) were able to counteract cell death induced by 6-OHDA in in vitro and in vivo PD models. Altogether, our results suggest that CtBPs are a good target to study transcriptional regulation mechanisms that modulate dopaminergic survival.