Periodic Reporting for period 1 - MemoryAggregates (Mechanism of Whi3 Aggregation and its Age-dependent Malfunction)
Période du rapport: 2020-09-01 au 2022-08-31
In this project (MemoryAggregates), our aim was to understand how cells control seemingly irreversible protein aggregation to their advantage, and how these control mechanisms are affected by ageing. We focused our investigation on a protein called Whi3, a known regulator of the cell cycle in yeast. Previous work in the lab had shown that yeast cells induce Whi3 aggregation in response to pheromone exposure that does not end in mating. This allows them to escape from the pheromone response, memorise a failed mating attempt, and avoid future mating attempts (Caudron and Barral, 2013). However, additional work in the lab had shown that Whi3 forms aggregates in old yeast cells, even if those cells are not exposed to pheromone (Schlissel et al., 2017). These key observations posed the question: how do young cells control Whi3 aggregation and how is this control affected by ageing?
This is a fundamental cell biology question, but it potentially has very important societal implications. Thanks to improved knowledge, resources and healthcare, the world’s population is ageing rapidly. Neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases will become a major burden on society, and there are no disease modifying treatments available. One of the key problems we will face is to understand the biology of these diseases. We will need to understand how ageing affects cells’ abilities to control protein assembly/aggregation processes.
An understanding of how cells control protein assembly/aggregation will have societal implications beyond healthcare. In synthetic biology, it will allow us to exploit the power of protein assembly to generate new functionalities, and conversely, to avoid unwanted protein aggregation.
Our overall objective was to understand the differences between Whi3 assemblies/aggregates that are induced by pheromone and ageing, what their functions are, and how the cell controls their formation.
Caudron, F. and Barral, Y. (2013) ‘A Super-Assembly of Whi3 Encodes Memory of Deceptive Encounters by Single Cells during Yeast Courtship’, Cell, 155(6), pp. 1244–1257. Available at: https://doi.org/10.1016/J.CELL.2013.10.046(s’ouvre dans une nouvelle fenêtre).
Schlissel, G. et al. (2017) ‘Aggregation of the Whi3 protein, not loss of heterochromatin, causes sterility in old yeast cells.’, Science (New York, N.Y.) 355(6330), pp. 1184–1187. Available at: https://doi.org/10.1126/science.aaj2103(s’ouvre dans une nouvelle fenêtre).
This is a fundamental cell biology question, but it potentially has very important societal implications. Thanks to improved knowledge, resources and healthcare, the world’s population is ageing rapidly. Neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases will become a major burden on society, and there are no disease modifying treatments available. One of the key problems we will face is to understand the biology of these diseases. We will need to understand how ageing affects cells’ abilities to control protein assembly/aggregation processes.
An understanding of how cells control protein assembly/aggregation will have societal implications beyond healthcare. In synthetic biology, it will allow us to exploit the power of protein assembly to generate new functionalities, and conversely, to avoid unwanted protein aggregation.
Our overall objective was to understand the differences between Whi3 assemblies/aggregates that are induced by pheromone and ageing, what their functions are, and how the cell controls their formation.
Caudron, F. and Barral, Y. (2013) ‘A Super-Assembly of Whi3 Encodes Memory of Deceptive Encounters by Single Cells during Yeast Courtship’, Cell, 155(6), pp. 1244–1257. Available at: https://doi.org/10.1016/J.CELL.2013.10.046(s’ouvre dans une nouvelle fenêtre).
Schlissel, G. et al. (2017) ‘Aggregation of the Whi3 protein, not loss of heterochromatin, causes sterility in old yeast cells.’, Science (New York, N.Y.) 355(6330), pp. 1184–1187. Available at: https://doi.org/10.1126/science.aaj2103(s’ouvre dans une nouvelle fenêtre).
The key work performed during this project includes:
- Assessing the specificity of Whi3 aggregation
- Whether post-translational modifications and RNA-binding influence Whi3 aggregation.
- Determining the composition and functions of Whi3 age-induced aggregates
- Determining how age-induced Whi3 aggregates affect ageing
- Beginning to identify key differences between age-induced and pheromone-induced Whi3 aggregates
Our results indicate that meso-scale protein assembly may be a widespread feature of ageing cells. We found that protein assembly processes are affected by ageing, but also affect ageing itself. Furthermore, the molecular compositions of protein assemblies can modulate the behaviour and lifespan of ageing cells.
- Assessing the specificity of Whi3 aggregation
- Whether post-translational modifications and RNA-binding influence Whi3 aggregation.
- Determining the composition and functions of Whi3 age-induced aggregates
- Determining how age-induced Whi3 aggregates affect ageing
- Beginning to identify key differences between age-induced and pheromone-induced Whi3 aggregates
Our results indicate that meso-scale protein assembly may be a widespread feature of ageing cells. We found that protein assembly processes are affected by ageing, but also affect ageing itself. Furthermore, the molecular compositions of protein assemblies can modulate the behaviour and lifespan of ageing cells.
A direct impact of our research is that it provides fundamental insights into the molecular mechanisms of ageing. Future work could be translated to other biological systems to determine how widespread such age-induced protein assembly is. Altering the molecular composition and properties of these assemblies could modulate healthy lifespan in other organisms beyond yeast.