Interplay of Endoplasmic Reticulum Stress and Autophagy in Parkinson’s Disease

• Autor(a) principal: Tavares, Carolina Leça de Azevedo Pereira
• 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/10362/26955
• topic: ER stress; Unfolded Protein Response; Autophagy; Parkinson’s disease; TUDCA; stress do RE; Doença de Parkinson; Autofagia; Domínio/Área Científica::Engenharia e Tecnologia

Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta, and by the accumulation of misfolded proteins. Evidence from studies in human PD brain indicates that endoplasmic reticulum (ER) stress and consequent unfolded protein response (UPR) are common features of the disease, placing ER dysfunction as an early component of PD pathogenesis. It is well established that autophagy is up-regulated in response to ER stress, probably as a compensatory mechanism. However, in the face of impaired UPR and autophagy, there is inefficient clearance, leading to protein accumulation that will result in development and progression of neurodegeneration. The main objective of this study is to evaluate the expression levels of ER stress and autophagy markers in C57BL/6 wild-type mice and N2a cells, a mouse neuroblastoma cell line, upon treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+), respectively. In parallel, mice and cells were also treated with Tauroursodeoxycholic acid (TUDCA), a chemical chaperone that modulates ER adaptive capacity, in order to assess if the neuroprotetive effect of this molecule results from modulation of autophagy. Finally, we seek to understand if TUDCA modulates the expression levels of glutathione-S-transferase pi (GSTp), an antioxidant enzyme. Expression of ER stress and autophagy markers was analysed using Western blot analysis and qPCR. Our results show that MPTP/MPP+ administration increases the expression of ER stress responsive genes and that this effect is attenuated with administration of TUDCA prior or after MPTP/MPP+ administration, namely by stimulation of autophagy. We also demonstrated by Western blot and immunocytochemistry that TUDCA increases the levels of GSTp. Together, our results suggest that TUDCA modulates ER stress by stimulation of UPR pathways as an early response and by stimulation of autophagy when ER stress is persistent, therefore TUDCA remains a promising therapeutic agent to be implemented in PD treatment.