Investigating the nexus between Ribonucleoprotein (RNP) granules and Tau during neuronal ageing

Ribonucleoprotein (RNP) granules are membrane-less organelles enriched in RNAs and RNA-binding proteins (RBPs). They are proposed to regulate RNA translation, localization, storage and decay and to play essential roles in neuronal function and maintenance. RNP granule biology closely associate with natural physiological ageing, but this association is mostly unexplored.

Tau is a protein implicated in the regulation of the cytoskeleton, best known for its involvement in neurodegenerative diseases including Alzheimer’s disease. This involves the detachment of Tau from microtubules into the cytoplasm, where Tau engages with atypical interactions. Also in normal ageing, Tau detaches from microtubules, and our data suggest that it engages in interactions with RNA-binding proteins. Interestingly, Tau is an intrinsically disordered protein able to partition into homotypic and heterotypic condensates via liquid-liquid phase separation (LLPS). RNP granules are also known to exist as condensates, which might suggest that Tau could be a component of RNP condensates impacting their normal function.

The aim of this project is to study the relations between Tau and a selection of identified RBPs known to be integral components of stress granules (SG) and processing bodies (PB). We will explore the impact that these interactions have on processes of brain ageing, using Drosophila as model organism. The approach you will use is highly inter-disciplinary by using: (a) genetic manipulations in Drosophila including loss-of-function, epistasis and rescue studies; (b) cell-culture and in vivo studies combined with cutting-edge bioimaging and readily established robust readouts to study the cell biology of neurons in different genetic backgrounds; (c) cutting-edge biochemistry and tools to study RNP granules/condensates in vivo; and (d) behavioural studies to investigate the physiological relevance of the mechanisms studied.

This PhD project addresses the urgent need to elucidate the complex cell biology of ageing nerve cells. As we age, neurons become increasingly frail which results in decreased functionality affecting social and cognitive interactions in the elderly, but we know too little about the mechanisms of neuronal atrophy. The proposed research will provide fundamental mechanisms of neuronal ageing.

This multidisciplinary project is a collaboration between the labs of Dr. Sanchez-Soriano (University of Liverpool) and Prof Mark Ashe (University of Manchester).