Pathophysiological role of the RNA-binding protein FUS in Dementia

Neurodegenerative conditions such as Alzheimer's Disease and frontotemporal dementia (FTD) exhibit a common pathophysiology undergoing synapse dysfunction and ultimately their elimination prior to greater neuronal atrophy. Consequently, a greater understanding of synapse function, and how this is dysregulated in the early stage of pathogenesis will bring further insights to identify potential novel therapeutic targets.



A key protein highly associated with FTD and ALS is fused in sarcoma (FUS). FUS is a ubiquitously expressed DNA/RNA-binding protein of the FET/TET family of multifunctional DNA/RNA binding proteins (Mackenzie, Rademakers & Neumann, 2010). FUS is also known to shuttle between the nucleus and the cytoplasm (Zinszner et al, 1997). FUS is also involved in the maintenance of dendritic spines, the small bulbous protrusions that receive most of the excitatory synaptic connections of the brain and underpin cognitive function (Kasai et al, 2003). Collectively, positioning FUS as a potential regulator of synapse function.



Interestingly, even though FUS mutations are presents in ALS patients, usually located in the proline-tyrosine NLS (PY-NLS), no FUS mutations have been identified in pure FTD/FTLD-FUS cases to date, raising questions about how and why non-mutant FUS may be exerting detrimental effects in these patients (Nolan, Talbot & Ansorge, 2016). However, the FUS condensates in FTLD patients exhibited hypomethylation of the FUS proteins, indicating a potential mechanism (Neumann et al, 2012).



Preliminary data from Cho group has revealed that overexpression of a FUS construct which mimics hypomethylation (FUS-16R; Qamar et al, 2018) in hippocampal CA1 neurons produces FUS condensates in dendritic spines, weakened AMPA- and NMDA-receptor mediated excitatory synaptic currents, and impaired synaptic plasticity (unpublished data 2022). These findings suggest FUS hypomethylation is sufficient to induce synaptic dysfunction, but the molecular pathways via with hypomethylated FUS exerts its toxic effects are unknown. Therefore, this proposed PhD project will test how FUS hypomethylation induces synapse dysfunction and may provide a molecular mechanism of pathophysiology in dementia.