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Stress granule dynamics in C. elegans neurodegeneration models

Primary Supervisor: Dr Zita Balklava, College of Health & Life Science

Secondary supervisor: Dr. Mariaelena Repici

PhD project title: Stress granule dynamics in C. elegans neurodegeneration models.

University of Registration: Aston University

Project outline:

Stress granules (SGs) are dense aggregations of proteins and mRNAs appearing in the cytosol under stressconditions. They are transient and dynamic structures and play a critical role in mRNA metabolism and translational control by modulating the stress response. RNA-binding proteins control the sequestration of mRNA within SGs upon induction of stress. SG formation represents a physiological response to stress, however chronic stresses associated with aging 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. elegansmutants 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 SG dynamics and role in neurodegeneration. 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 in these mutants compared to wild type worms using live cell imaging and fluorescence and confocal microscopy at different time points throughout the lifetime of the animals.

Objective 2: Investigate whether modulation of SG formation affects AD and PD disease phenotypes. 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. Different metrics (life-span analysis, gentle touch behaviour, fecundity, distal germline size analysis, etc.) will be used to evaluate the resulting single and double mutant worms.

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.

Key references:

  1. Wolozin, B. and Ivanov, P. (2019). Stress Granules and neurodegeneration. Nat Rev Neurosci, 11, 649-666, doi: 10.1038/s41583-019-0222-5.
  2. 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

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour & Integrated Understanding of Health:Ageing

    Techniques that will be undertaken during the project:

    Genetic manipulations using transgenic technologies in C. elegans.

    Molecular biology to construct RNA-mediated interference feeding vectors to analyse loss-of-function phenotypes.

    C.elegans disease-related phenotype and behaviour analyses throughout lifetime of the animals.

    Fluorescence microscopy and image analysis.

    Contact: Dr Zita Balklava, Aston University