Unraveling client selectivity and pattern recognition of DNAJ molecular chaperones inhibiting intracellular polyglutamine aggregation in neurodegenerative models

• Applicant: Dr. Gaetano Calabrese
• Subject Area: Biochemistry ; Cell Biology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 446508933

Many neurodegenerative disorders are characterized by the accumulation of proteins forming toxic aggregates inside neurons. Certain proteins contain regions with a long series of repeated of the same glutamine amino acid, otherwise known as polyglutamine regions (polyQ), that favor the aggregation process. In the cell, the molecular chaperone system maintains a fully operational protein environment by helping proteins reach and retain their final structure, prerequisite for their functionality. Interestingly, two molecular chaperones of the DNAJ family (DNAJB6 and DNAJB8) were recently identified to prevent protein aggregation and prolong the lifespan in Parkinson´s and Huntington’s disease mouse models, making them interesting potential therapeutic targets.Our goal is to better understand how these two chaperones have evolved by identifying which proteins inside the cell require them for proper folding. We will use cutting edge mass spectrometry approaches to identify which proteins interact with the two chaperones and require them for folding. Identification of the repertoire of the so called “client” proteins, together with the determination of a specific pattern on the client proteins recognized by the two chaperones could potentially lead to the identification of new target candidates that can either favor or inhibit polyQ aggregation by modulating DNAJB6/8 anti-aggregation activity. This will allow the potential design of new therapeutic approaches for the treatment of amyloid-based neurodegenerative diseases.

• DFG Programme: WBP Fellowship
• International Connection: Canada
• Host: Professor Dr. Thibault Mayor