Altered RNA metabolism in neurodegeneration

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

A wide variety of neurodegenerative diseases are caused by mutations in RNA binding proteins. However, the pathogenic mechanisms leading to these disorders are not yet well understood. We study the FUS gene (Fused in Sarcoma), which encodes a conserved RNA-binding protein. Mutations in this gene can lead to the development of Amyotrophic Lateral Sclerosis (ALS), the most common motor neuron (MN) disease in human adults. While FUS is a nucleocytoplasmic shuttling protein, it is mainly nuclear at steady state. Most ALS-associated FUS mutations disrupt the nuclear localization signal (NLS), leading to nuclear exclusion and cytoplasmic FUS aggregates in neurons and glial cells of these ALS patients. FUS is also a major protein component in pathologic cytoplasmic inclusions in some cases of Frontotemporal Lobar Degeneration (FTLD-FUS). However, unlike for FUS-linked ALS, the molecular cause for cytoplasmic mislocalisation in FUS-linked FTLD is unknown and no vertebrate model for FTLD-FUS is available. Therefore, the potential pathomechanisms in FUS-linked FTLD will have to be inferred from the insights from FUS-linked ALS models and its physiological functions.
FUS functions in several processes required for proper gene expression, such as transcription, pre-mRNA splicing, and miRNA processing. However, its precise role in these processes and most of its targeted RNAs are, as of yet, unknown. The combination of this lack of knowledge with the lack of FTLD-FUS models has led me and my research group to the conviction that understanding the biological function(s) of normal FUS will be one of the keys to gain insight into the role of FUS-associated neurodegeneration. Furthermore, this will allow us to fully interpret our results from our parallel investigation on the pathomechanisms of FUS-linked ALS using in vitro and in vivo models of disease. The results of our research are expected to reveal the molecular mechanisms implicated FUS-associated ALS and FTLD and identify targets for the development of therapeutic approaches.