Identification of plasma membrane import routes of Tau, FUS and alpha-synuclein disaggregating compounds using yeast based high-content screening

• Grant number: 18/09194-6
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): June 11, 2018
• Effective date (End): September 10, 2018
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Elizabeth Bilsland
• Grantee: Ludimila Dias Almeida
• Supervisor: Per Sunnerhagen
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Research place: University of Gothenburg, Sweden
• Associated to the scholarship: 17/01986-8 - Determination of substrate specificity of plasma membrane transporters from Saccharomyces cerevisiae and Homo sapiens, BP.DR

Abstract

The drug development for diseases that affect the Central Nervous System (CNS) should consider the transport of the compound through the human Blood Brain Barrier (BBB). Due to the protective function of this barrier, the entrance of xenobiotic molecules is restricted and occurs preferentially via membrane carriers present in the BBB cells. Hence, the development of methodologies for the study of how these compounds cross the membrane is essential for the development of drugs that efficiently target the CNS. Saccharomyces cerevisiae is a well-studied organism for which complete collections of gene deletions are available for high-throughput experiments, such various drug screening approaches. A strategy already well established in our group is a screening method for drug uptake using a library of single deletions of the genes encoding each of the non-essential S. cerevisiae plasma membrane transporters. Our rationale is to identify how drugs may cross the yeast plasma membrane and translate these findings to the orthologue transporters of the human BBB. In this context, we will focus on the identification of novel compounds targeting three diseases that affect the CNS: Amyotrophic lateral sclerosis (ALS), Alzheimer's and Parkinson's diseases. We have selected 1,000 molecules that represent the diversity of the DIVERSet-EXP library (ChemBridge Corporation), and will screen these for inhibitors of human FUS, TAU and ±-synuclein aggregation in yeast-based high-content screens. Once we have identified compounds capable of inhibiting human protein aggregation, we will identify which carriers are responsible for their entry into yeast cells. This knowledge will be used to identify putative human BBB transporters that could potentially promote the uptake of novel compounds to treat ALS, Alzheimer's and Parkinson's diseases. (AU)