BAG2 AND THE IMMUNEPROTEASOME SYSTEM IN ALZHEIMERS DISEASE: FROM BIOINFORMATICS TO CELL CULTURE TESTING

• Grant number: 24/09041-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2024
• Status: Discontinued
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Daniel Carneiro Carrettiero
• Grantee: Mariana Arsky Gomes
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
• Associated research grant: 23/05075-0 - BAG2 condensates: Degradation and Antigen presentation, AP.R
• Associated scholarship(s): 25/00521-8 - BAG2 IN INFLAMMATION: INSIGHTS FROM HIGH RESOLUTION IMAGING, BE.EP.IC

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease, with old age being the greatest risk factor. Its sporadic form accounts for 90% of AD cases. The cognitive decline strongly correlates with aggregated forms of TAU protein, hallmark of AD and other tauopathies. The accumulation of these aggregates could be due to defects in protein degradation mechanisms, like the proteasome. Proteasome dysfunction has been reported in many neurodegenerative diseases and its activity declines with age. Our group described in 2009 a highly efficient TAU protein degradation pathway through the proteasome that is ubiquitin-independent and mediated by the co-chaperone BAG2. Recently (2022), we demonstrated a close relationship between BAG2 and the PA28 cap of the proteasome, a structure that is extremely important for the functioning of the immunoproteasome. It is interesting to note that this provides peptides for antigen presentation in the major histocompatibility complex (MHC). It is also known that interferon-gamma (IFN-³) stimulates this pathway. Preliminary results from our group suggest that IFN-³ modulates the BAG2 protein, but the relationship between this modulation and the antigen presentation system is still unknown. It is possible that TAU peptides are presented by the MHC-1 system modulated by BAG2 and stimulated by IFN-³. Therefore, the present study aims to investigate the link between the BAG2 mediated degradation and the antigen presentation system. For this, target genes involved in protein degradation and antigen presentation will be identified using a single-nucleus RNA sequencing database from sporadic Alzheimer diseased patients. Next, we will test the effects of IFN-³ in H4 and CRISPRi-BAG2 cells in culture on these identified targets, through real-time qPCR and Western Blot.