The co-chaperone Bag2: the importance of liquid droplets for the Alzheimer's disease

• Grant number: 19/22708-1
• Support Opportunities: Scholarships abroad - Research
• Start date: July 01, 2020
• End date: June 30, 2021
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Daniel Carneiro Carrettiero
• Grantee: Daniel Carneiro Carrettiero
• Host Investigator: Kenneth Kosik
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
• Institution abroad: University of California, Santa Barbara (UC Santa Barbara), United States

Abstract

Alzheimer's disease (AD), the most frequent cause of progressive dementia associated to aging, is a public health with worldwide global repercussion. Until today, this disease is considered not curable and the available treatments are limited in its ability to altering its progression. Histological post mortem analysis show that brain from AD patients present the accumulation of two proteins in its insoluble forms: 1) amyloid beta peptide (A²), present in the senile plaque found at the extracellular compartment and 2) Tau protein, which aggregates in the intracellular compartment as neurofibrilary tangles. Those Tau inclusions are formed by hyperphosphorilated Tau protein labeled by ubiquitin. The presence of those ubiquitin inclusions suggests Tau proteolitic defects, as ubiquitinated proteins should be directed to the proteosome-ubiquitin dependent pathway (UPS). This system works through a proteic complex using the chaperones CHIP/Hsp70 which has an active role in the Tau molecule fate inside the cell. The Bag2 protein (Bcl2-associated athanogene 2), known to inhibit the CHIP E3 ligase activity, favors Tau protein degradation via ubiquitin-independent pathway through protesosome and catalytic ATPase-activity of Hsp70. This study was published by our group in 2009 (J Neurosci 29(7): 2151-61, 2009). In this same study, we have shown the presence of spherical structures containing Bag2 which associated to the microtubules. The functionality of those structures remains unknown up to nowadays. Recently, the literature started to describe membraneless organelles named "liquid droplets". They are formed by high density of a number of molecules in liquid state that separates from another liquid through intermolecular electrostatic interactions. This phenomena is described as liquid-liquid phase separation (LLPS), and has been demonstrated to be of great relevance for a number of neurodegenerative diseases, such as AD, Parkinson´s disease, amiotrophic lateral sclerosis, all of which has the common feature of developing protein aggregates. Furthermore, it seems that the presence of LLPS may play a role in a number of different biological processes. Many proteins may undergo LLPS such as TIA-1 and 3GBP1 in the formation of stress granules, the FUS protein, hnRNPA1 and TDP-43. We believe that the round structures of Bag2 observed back in 2009 are liquid droplets of Bag2 with a not yet described function. Our preliminary results indeed indicate that indeed Bag2 undergoes LLPS. Thus, the aim of the present study is to study and functionally characterize the Bag2 droplets. This study will bring a significant impact for the AD research field, considering that Bag2 has a central role in toxic Tau degradation. (AU)