The influence of molecular chaperones on alpha-synuclein aggregation in model biomolecular condensates

• Grant number: 23/12135-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: March 01, 2024
• End date: February 28, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Physical-Chemistry
• Principal Investigator: Carlos Henrique Inacio Ramos
• Grantee: Marcos Vinícius Aquino Queirós
• Supervisor: Evan Spruijt
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Radboud University Nijmegen, Netherlands
• Associated to the scholarship: 22/10151-5 - Study of the association of chaperones on the formation of coacervates used as membraneless organelles models, BP.PD

Abstract

Molecular chaperones play an important role in protein quality control and are pivotal in protein folding processes. In recent years, it has been discovered that chaperones participate in many membraneless organelles (MLOs). These MLOs are also known as biomolecular condensates and compartmentalize proteins and nucleic acids without lipid membranes, unlike typical vesicle-like organelles. The formation of MLOs is usually driven by liquid liquid phase separation (LLPS) of certain disordered proteins and nucleic acids, but partitioning of guest molecules, including chaperones, gives rise to a rich and diverse compositional diversity. To explore the role of chaperones in MLOs, we propose to study the partitioning of two different molecular chaperones, Hsc70 and DNAJA1, in coacervate droplets as models of biomolecular condensates. The activity of the chaperones will be investigated by studying their influence on the amyloid formation of ±-synuclein (±-Syn). This pre-synaptic protein has attracted attention because its aggregated species have been found in intraneuronal inclusions and are highly associated with Parkinson's disease. We will use a variety of fluorescence spectroscopy and microscopy techniques to study the partitioning of the chaperones in the absence and presence of ±-Syn, and the influence of chaperones on the spatiotemporal distribution of ±-Synand ±-Syn aggregation kinetics. We anticipate that our results provide useful insights into the role of Hsc70 and DNAJA1 in MLO behavior and ±-Syn aggregation. (AU)