Title: LMB - CoEN 2016 - Using C. elegans to understand seeding and spreading of tau aggregation
Funder: Medical Research Council

Abstract: Tau aggregation is a prominent feature of many neurodegenerative diseases, including Alzheimer’s disease (AD), for which the most prominent risk factor is ageing. The reasons underlying the age-associated nature of disease progression are not yet understood. Recent evidence suggests that tau aggregation can be seeded and propagates in a prion-like manner, by mechanisms that are also currently unclear. We aim to develop C. elegans models that will enable us to determine pathways underlying the seeding and spreading of tau aggregation, providing insights that could potentially be used for the development of novel therapeutics against tauopathies. Aim 1: Do aged worms contain misfolded proteins that can seed tau aggregation? Ageing is the most prominent risk factor for development of AD, and is associated with a strong decline in proteostasis capacity, leading to prominent aggregation of part of the proteome in the absence of disease. We will look at the role of non-disease-associated proteins that aggregate as a normal part of ageing, in seeding aggregation of tau. This will enable us to understand the critical role of ageing in the initiation of AD. We will use RNAi to knock down candidate proteins known to aggregate with age, in tau-expressing C. elegans, to determine whether this influences age-associated tau-induced loss of motility. If so, we will then use an in vitro tau aggregation assay to determine whether insoluble protein extracts from aged C. elegans, with and without knockdown of the candidate aggregative proteins, can seed tau aggregation. Aim 2: Can tau pathology spread between cells in C. elegans? There is currently a shortage of genetically-tractable in vivo models for the prion-like cell-cell spreading of tau aggregation. We aim to create such a model in C. elegans, giving us the ability to screen and manipulate genes and pathways in order to determine their role in the propagation of tau aggregation. This novel model would be a valuable tool towards understanding the spreading of tau pathology. Aim 3: Can manipulation of aggregation-seeding proteins or proteostasis pathways influence spreading of tau aggregation? We currently have little understanding of the mechanisms that influence the cell-to- cell spreading of tau aggregation. We aim to explore the role of genes found to promote age- associated seeding of tau aggregation (Aim 1) in the cell-to-cell spreading of tau aggregation in a novel C. elegans model (Aim 2). In addition, a pathway involved in protein homeostasis that has been closely associated with AD, the UPRER, has been recently shown to spread cell non-autonomously, suggesting that it may play a role in the spreading of tau pathology. We will therefore utilize our C. elegans tau model to explore the effect of activating two branches of the UPRER on tau aggregate spreading. We will then confirm these insights in a human cell culture seeding model of tau aggregation. We believe these experiments will significantly enhance our knowledge of the factors involved in the spreading of tau pathology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL