Characterization of the effect of Latrepirdine in models of alpha-synuclein overexpression
Scientific evidence suggests that the accumulation of α-synuclein (α-syn) protein could contribute to the formation of proteotoxics species, mitochondrial dysfunction and neurodegeneration observed in Parkinson's disease (PD) and other synucleinopathies. Although the exact mechanism of neurotox...
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| Formato: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | Chile |
| OAI Identifier: | oai:repositorio.anid.cl:10533/208861 |
| Acesso em linha: | https://hdl.handle.net/10533/208861 |
| Access Level: | acceso abierto |
| Palavra-chave: | Medicina y Ciencias de la Salud Biotecnología Médica Biología Celular |
| Resumo: | Scientific evidence suggests that the accumulation of α-synuclein (α-syn) protein could contribute to the formation of proteotoxics species, mitochondrial dysfunction and neurodegeneration observed in Parkinson's disease (PD) and other synucleinopathies. Although the exact mechanism of neurotoxicity and the identity of the toxic species of α-syn involved in neurodegeneration has not been clarified, recent research suggests that an increase in the concentration of α-syn, due to an increase in expression and / or due to the failure of mechanisms of proteostasis, promote the formation of soluble oligomers non-fibrillar of the protein, which would be responsible for synaptic dysfunction and neuronal degeneration observed in PD. The α-syn protein is degraded by the ubiquitin-proteasome system and autophagic-lysosomal pathway, which involves mechanisms of macroautophagy, microautophagy and selective chaperone-mediated autophagy (CMA). Increased levels of α-syn and deficiencies in the activity of these protein degradation systems have been detected in brain and tissue of sporadic PD patients suggesting that a deficiency in the proteostasis of α-syn might be relevant in the development of disease. Current treatments for PD and other synucleinopathies are only symptomatic, and there are no therapeutic strategies that have proven to slow the neurodegenerative process. In this context, it has been suggested that the control of the concentration of α-syn, by inhibiting its synthesis or increased degradation, could be an important therapeutic strategy in decreasing the progression of dysfunction and neuronal death, besides contributing delay symptomatic progression of disease. A study during this work show that Latrepirdine, a molecule of the beta-carbolines family, reduce cytotoxicity by overexpression induced α-syn in neuronal cell line SH-SY5Y and is able to decrease the overall levels protein. Furthermore, it was found that the decrease in α-syn induced by Latrepirdine is mediated by a post-translational dependent lysosomal activity mechanism and Latrepirdine induce the selective activation of AMC at nanomolar concentrations, this being the first report of a molecule that activates the AMC. |
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