Study of alpha-synuclein in MAMs: the role of mortalin and transglutaminase 2 in the stressful condition induced by mutated alpha-synuclein.

• Grant number: 16/05580-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: July 01, 2016
• End date: June 30, 2017
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Soraya Soubhi Smaili
• Grantee: Adolfo Garcia Erustes
• Supervisor: Mauro Piacentini
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: Università degli Studi di Roma Tor Vergata, Italy
• Associated to the scholarship: 13/20976-2 - Development, characterization and studies of autophagy and apoptosis in a Parkinson's Disease cell model, BP.DR

Abstract

The main pathological hallmark of Parkinson's disease (PD) is the presence of aggregates formed by the protein alpha-synuclein called Lewy Bodies. Two point mutations on alpha-synuclein gene (SNCA) lead to the formation of mutated proteins, A30P and A53T, both related to familial Parkinson's disease. According to several evidences, alpha-synuclein binds to mitochondrial complex I, promoting the decrease of ”qm, Ca2+ release and release of pro-apoptotic factor stored at mitochondrial inter-membrane space. However, reports have demonstrated a new location of alpha-synuclein in a region denominated MAMs (mitochondria-associated ER membranes) that is a sub-domain of endoplasmic reticulum which interacts with mitochondria. In MAMs alpha-synuclein can interact with several proteins, Ca2+ receptors and channels, mortalin, TG2, IP3R3 and VDAC. The aim of this work is to functionally characterize the interaction among these proteins and the alpha-synuclein or its mutants, by western blot and immunoprecipitation analysis, siRNA or knock-out cells. Aspects related to Ca2+ signaling and homeostasis, as well as mitochondrial dynamics and mitophagy will also be evaluated using fluorescence methods. The understanding of alpha-synuclein interactions with TG2 and mortalin and their role in PD may clarify the mechanism whereby this protein promotes cellular dysfunctions, which can lead neurons to death in PD.

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)

ERUSTES, ADOLFO GARCIA; D'ELETTO, MANUELA; GUARACHE, GABRIEL CICOLIN; URESHINO, RODRIGO PORTES; BINCOLETTO, CLAUDIA; DA SILVA PEREIRA, GUSTAVO JOSE; PIACENTINI, MAURO; SMAILI, SORAYA SOUBHI. Overexpression of alpha-synuclein inhibits mitochondrial Ca2+ trafficking between the endoplasmic reticulum and mitochondria through MAMs by altering the GRP75-IP3R interaction. Journal of Neuroscience Research, v. 99, n. 11, SEP 2021. (19/02821-8, 16/05580-3, 17/10863-7, 13/20073-2, 19/14722-4, 16/20796-2)