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Are oxysterols able to modify ubiquitin and inhibit the proteolytic pathway by blockage of the ubiquitin proteasome system?

Grant number: 14/14801-8
Support type:Regular Research Grants
Duration: November 01, 2014 - October 31, 2016
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Miriam Uemi
Grantee:Miriam Uemi
Home Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
Assoc. researchers:Marilene Demasi ; Roberto Kopke Salinas ; Sayuri Miyamoto

Abstract

Neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewis body dementia, Amyotrophic Lateral Sclerosis and others are characterized by abnormal deposition of insoluble protein aggregates or inclusion within neurons and is associated with accumulation of ubiquitinated proteins in neuronal inclusions. Accumulations of ubiquitinated proteins and protein aggregates could be achieved by several mechanisms including mutations, overproduction or impairment of their degradation. Inhibition of the normal protein degradation pathway is produced by blockage of the ubiquitin proteasome system (UPS). The ubiquitinated protein aggregates are believed to result from dysfunction of the UPS pathway caused by damaging events, such as oxidative stress and production of neurotoxic molecules or from structural changes of protein substrates which prevent their recognition and degradation by the UPS. The relationships between these events are not well established, however it is believed that they are related with oxidative stress conditions. In oxidative stress condition, reactive oxygen species (ROS) are generated and react with biological targets generating new products, and some of them are citotoxic for the cell, generating damage in biological systems. The reaction of proteins with ROS can disrupt the active sites of enzymes or affect the conformation of structural proteins altering their function. In this context, this project proposes to study structural changes in proteins starting with ubiquitin caused by products of oxidative stress identified with abnormal concentration in neurodegenerative disorders and how these modifications might impair the UPS function, using nuclear magnetic resonance spectroscopy and mass spectrometry. (AU)