Towards understanding the role of oxidized lipid membrane on amyloidogenic diseases: biophysical and structural characterization of membrane-induced GAPDH protofibrils

• Grant number: 14/50766-2
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2015
• End date: June 30, 2017
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Agreement: CONICET
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Rosangela Itri
• Grantee: Rosangela Itri
• Principal researcher abroad: Rosana Chehin
• Institution abroad: Universidad Nacional de Tucumán (UNT), Argentina
• Host Institution: Instituto de Física (IF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 12/50680-5 - Photosensitization in life sciences, AP.TEM

Abstract

Early oligomeric species of different proteins have recently acquired biological relevance since some of them have been linked to neurotoxic or neuroprotective activity in neurodegenerative diseases. However, only few models of these species have been proposed and thus the molecular mechanisms underlying their biological activity remain unclear. In particular, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a multifunctional enzyme that has been associated to neurodegenerative diseases, is found to be colocalized with a-synuclein in amyloid aggregates in post-mortem tissue of patients with sporadic Parkinson disease. In a previous work, we showed that in vitro heparin can trigger GAPDH amyloid aggregation and that prefibrillar species, structurally characterized by SAXS combined with all-atom model, can abolish the toxicity of a-synuclein species in neuroblastoma cells. In the present project, we intend to investigate comparatively the GAPDH aggregation mechanism in the presence of membranes composed of oxidized lipids (hydroperoxides and truncated ones) in the absence and presence of negatively charged lipids, in respect to the structurally derived heparin-induced GAPDH oligomer. The relevance of this study is focused on deciphering the role that oxidized lipids may exert on protein aggregation and analyses the possible implication of membrane-related oxidative stress on amyloid genesis, in particular, on Parkinson disease. (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)

GONZALEZ-LIZARRAGA, FLORENCIA; SOCIAS, SERGIO B.; AVILA, CESAR L.; TORRES-BUGEAU, CLARISA M.; BARBOSA, LEANDRO R. S.; BINOLFI, ANDRES; SEPULVEDA-DIAZ, JULIA E.; DEL-BEL, ELAINE; FERNANDEZ, CLAUDIO O.; PAPY-GARCIA, DULCE; et al. Repurposing doxycycline for synucleinopathies: remodelling of alpha-synuclein oligomers towards non-oxic parallel beta-sheet structured species. SCIENTIFIC REPORTS, v. 7, FEB 3 2017. (14/50766-2)