Deciphering the role of stress response in neurodegeneration

Project Outline

Stress granules (SGs) are dense aggregations of proteins and mRNAs appearing in the cytosol under stress conditions. They are transient and dynamic structures and play a critical role in mRNA metabolism and translational control by modulating the stress response. SG formation is transient and represents a physiological response to stress, however chronic stresses associated with aging and neurodegeneration lead to formation of persistent SGs that contribute to aggregation of disease-related proteins.

SGs dynamics have been mainly studied in yeast or human cell lines and not enough information is available on stress granules in multicellular organisms. C. elegans represents a powerful model to study neurodegeneration and dissect molecular mechanisms and signaling pathways contributing to pathology. An array of established C. elegans mutants can give insight into different aspects of neurodegenerative disease pathogenesis. Similarly, several tools are now available to study the role of cytoplasmic stress granules in stress response in C. elegans.

The aim of this project is to use C. elegans models for neurodegenerative diseases (Alzheimer’s Disease (AD) and Parkinson’s Disease (PD)) to investigate stress response and SG dynamics and role in neurodegeneration in young and aging adults. This will be achieved through the following objectives: Objective 1: Analyse SG dynamics in C. elegans AD and PD models using fluorescently labelled SG markers. For this objective GFP-tagged SG markers TIAR-1 and GTBP-1 will be crossed into AD and PD mutant worms and SG dynamics will be analysed using fluorescence microscopy at different time points throughout the lifetime of the animals in the presence and absence of acute stress. Objective 2: Investigate whether modulation of SG formation affects AD and PD disease phenotypes and general worm fitness indicators. This objective will be achieved by crossing loss-of-function mutations of SG key proteins TIAR-1 and GTPB-1 into mutant AD and PD worms and analysing the resulting phenotypes at different time points throughout the lifetime of the animals. Together these objectives will allow to understand whether SGs play a crucial role in AD and PD pathogenesis and potentially suggest novel therapeutics for neurodegeneration.

References

Wolozin, B. and Ivanov, P. (2019). Stress Granules and neurodegeneration. Nat Rev Neurosci, 11, 649-666, doi: 10.1038/s41583-019-0222-5.

Van Pelt, K. M. and Truttmann, M.C. Caenorhabditis elegans as a model system for studying aging-associated neurodegenerative diseases. Translational Medicine of Aging, 4, 60-72, https://doi.org/10.1016/j.tma.2020.05.001

Techniques

• Genetic manipulations using transgenic technologies in C. elegans.
• C. elegans disease-related phenotype and behavioural analyses.
• Fluorescence microscopy and image analysis