Development, characterization and studies of autophagy and apoptosis in a Parkinson's Disease cell model

• Grant number: 13/20976-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: February 01, 2014
• End date: August 01, 2018
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Soraya Soubhi Smaili
• Grantee: Adolfo Garcia Erustes
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 16/05580-3 - Study of alpha-synuclein in MAMs: the role of mortalin and transglutaminase 2 in the stressful condition induced by mutated alpha-synuclein., BE.EP.DR

Abstract

The main pathological feature of Parkinson's disease (PD) is the presence of intracitoplasmatic protein aggregates called Lewy Bodies, whose main component is the protein alpha-synuclein on its fibrilar conformation. In the 1990's, two mutations in the gene that encodes alpha-synuclein (SNCA) were described. These mutations lead to transcription of mutant proteins, A30P and A53T, both of them related to genetic cases of PD. Increasing in the concentration of these proteins on neuronal cytoplasm may cause mitochondrial dysfunctions, since it is suspected that these proteins bind to mitochondrial membrane and then inhibit the complex I of electronic chain. It causes decoupling of mitochondrial membrane whose consequences are the decrease in membrane potential, inhibition of ATP syntheses, increase in mitophagy signaling and induction of apoptotic process. Our previous results show that alpha-synucleins may modulate the mitophagic process and inhibit autophagy besides increasing apoptosis. Thus, the aim of this project will be to establish and to characterize a cellular lineage that overexpresses the gene of alpha-synuclein wild type or its mutants A30P and A53T permanently. Once these lineages are established, we intend to evaluate the interaction of alpha-synucleins with mitochondrial structures as well as featuring the modulation of the autophagic and mitophagic processes. Furthermore, we are supposed to study the participation of PINK/Parkin proteins on these processes and their relation to the ion Ca2+. For this purpose, lentiviral production and infection techniques will be used with vectors containing the SNCA gene, high resolution fluorescence microscopy in real time and space, confocal microscopy of high resolution and protein expression by Western Blot analysis. The study of these cellular pathways will help in better understanding the PD pathogenesis. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

COSTA, ANGELICA JARDIM; ERUSTES, ADOLFO GARCIA; SINIGAGLIA, RITA; NEVES GIRARDI, CARLOS EDUARDO; DA SILVA PEREIRA, GUSTAVO JOSE; URESHINO, RODRIGO PORTES; SMAILI, SORAYA SOUBHI. Lack of Autophagy Induction by Lithium Decreases Neuroprotective Effects in the Striatum of Aged Rats. PHARMACEUTICS, v. 13, n. 2, FEB 2021. (17/10863-7, 12/08273-3, 16/20796-2, 13/20073-2, 13/20976-2)