Title : Application of activity-based probe, MV151, in the mammalian nervous system reveals new insight into proteasome changes in human Alzheimer’s disease brain
Proteasome complexes play a critical role in human brain health and disease. Despite enormous effort, a deep understanding of proteasome composition, activity, and abundance in the human brain remains poorly understood. Here, we describe a series of tools that can measure the catalytic activity and levels of individual proteasome β-subunits and distinct proteasome complexes in mammalian tissue. Adapting these tools to brain tissue from human Alzheimer’s disease (AD) patients, we found that the human brain has a high abundance of catalytically active 20S proteasomes and that these 20S proteasomes exhibit higher total activity in AD when compared to unaffected controls. Additionally, we showed that 20S proteasome abundance is inversely correlated with the severity of the AD case. Taken together, these data indicate that while 20S proteasome abundance is decreasing in AD patient brains, this is counter-balanced by an increase in proteasome activity. We now propose that homeostasis of 20S proteasome activity is a hallmark of human brain health, and changes in abundance and activity are correlated to the severity of AD disease. This discovery sets the stage for further investigation into 20S proteasome activity in neurodegenerative disease states.
What will audience learn from your presentation?
- I will present a novel application of multiple proteasome tools to study the proteasome composition, abundance, and activity using purified proteasome, mouse brain tissues, and neuronal cultures to inform our efforts to study proteasome biology in human AD patient brains
The audience will learn how to adapt this new approach to studying proteasome biology in different model organisms and across different tissues/disease states.
- Studying proteasome activity in postmortem human brain tissue has been very challenging. The audience will be able to incorporate this new approach to their studies to study protein degradation in human tissue samples.
- One of the hallmarks of neurodegenerative diseases (NDs) is the impairment of proteasome-dependent protein degradation pathways. The link between proteostasis and ND progression is an active area of investigation. The audience will be able to design experiments with the activity-based probe used in this study to investigate proteasome activity in various NDs (such as AD, HD, PD, etc.).