| Grant number: | 23/05075-0 |
| Support Opportunities: | Regular Research Grants |
| Start date: | February 01, 2024 |
| End date: | January 31, 2026 |
| Field of knowledge: | Health Sciences - Medicine - Psychiatry |
| Principal Investigator: | Daniel Carneiro Carrettiero |
| Grantee: | Daniel Carneiro Carrettiero |
| Host Institution: | Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil |
| Associated researchers: | Emidio Beraldo Neto ; Kenneth Kosik ; Maria Camila Almeida |
| Associated scholarship(s): | 24/09041-6 - BAG2 AND THE IMMUNEPROTEASOME SYSTEM IN ALZHEIMERS DISEASE: FROM BIOINFORMATICS TO CELL CULTURE TESTING, BP.IC |
Abstract
The most common cause of dementia among older adults, Alzheimer's disease (AD), affects more than 50 million people worldwide, and will grow to a projected 150 million in 2050. The brain of these patients is characterized by the accumulation of insoluble protein aggregates, which suggests defects in the intracellular degradation machinery. In collaboration with the University of California (UCSB), we recently describe the existence of a new membranless cytoplasmic degradation organelle called "Bag2 condensates". This organelle appears during stress by the liquid-liquid phase transition phenomena. Stress condenses hundreds of functional units where each one contains several components capable of mediating the processes of ubiquitin-independent protein degradation (UIPS). Among the components described are the co-chaperone Bag2, the chaperone Hsp70 and the 20S proteasome activated by members of the PA28 family (PMSE).Our hypothesis for this project is that these small functional units of "Bag2 condensates" could also be involved in the cellular immune response, specifically the antigen-presenting system which includes a risk factor for AD. This idea is based on preliminary data where IFN-gamma not only induces Bag2 condensation but also increase the expression of the PSMB8 that co-localizes with Bag2. It is known that IFN-gamma swap some subunits of the 20S proteasome for others such as the PSMB8, forming the immunoproteasome. It associates with the endoplasmic reticulum (ER) transferring small fragments of the cleaved client to the MHC class I complex that will be transported to the cell surface where they will then be presented to immune T cells. These cells are known to recognize and destroy cells containing dysfunctional proteins. We found evidence to suggest that "Bag2 condensates" could be present in the ER during stress. We also want to investigate the potential role of "Bag2 condensates" in the extracellular space. This new concept is based on previous evidence that "Bag2 condensates" were visualized in the extracellular matrix in cultured cells. Bag2, Hsp70 and the 20S proteasome itself were described extracellularly, the same components found in the "Bag2 condensates". What would be the function of these extracellular "Bag2 condensates"? Activation of the immune system? Extracellular degradation? This work will be of great value for both the understanding of the mechanisms of antigen presentation mediated by the liquid-liquid phase transition in the intra- and possibly extracellular space as well as for the clinical pharmacology with a possible role of "Bag2 condensates" as a biomarker for neurodegenerative diseases. (AU)
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