Study of the modulation of the physicochemical characteristics of alpha-synuclein by interaction with chaperones and co-chaperones

• Grant number: 24/13816-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Carlos Henrique Inacio Ramos
• Grantee: Rebeca Cristian Victor Morada
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Alpha-synuclein (a-syn) is a protein of 140 amino acid residues that plays multiple roles in the synaptic activity of vertebrates. Adverse conditions or mutations can lead to the polymerization of this protein into amyloid fibrils, which are associated with certain neurodegenerative diseases known as synucleinopathies. For example, a-syn is one of the main components of amyloid plaques in Alzheimer's disease and is the principal component of Lewy bodies. It is known that a-syn is an intrinsically disordered protein, exhibiting various conformations during the aggregation process. Recently, it was discovered that its phase separation into droplets can initiate this process. Molecular chaperones, which play a crucial role in regulating cellular proteostasis as part of the protein quality control (PQC) system, are potential interactors of a-syn. Studies have shown that inhibition of certain chaperones can stimulate the formation of amyloidogenic a-syn in cells. This project aims to characterize the interaction between a-syn and various chaperones and co-chaperones, as well as study the modulation of aggregate formation and phase transition of a-syn. To achieve this goal, we will leverage our extensive experience in the study of proteins, including structure, function, aggregation, and phase transition, especially in chaperones, including expression, purification, activity, and mutations, as well as in a-syn, covering expression, purification, NMR labeling, mutations, coupling with fluorescent probes, aggregation, and phase transition. The results of this study have the potential to build a model for the action of molecular chaperones in the mechanisms regulating a-syn function and aggregation, potentially providing advanced knowledge to rationalize proposals for therapeutic interventions in synucleinopathies. (AU)