Abstract Body

ALS and FTD are fatal and incurable neurodegenerative diseases, characterized by accumulation of pathologic forms of RNA-binding proteins, predominantly TDP-43 and FUS. The functional consequences and potential neurotoxic effects of these FUS or TDP-43 aggregates observed in postmortem brains are debated. Combining structural protein analysis with cellular systems we uncovered a novel and unexpected mechanism that counteracts pathologic aggregation of TDP-43 (1). We also recently discovered that FTD heterogeneity is associated with alternate pathological TDP-43 conformations, reminiscent of prion strains (2). Moreover, we recently showed that cytoplasmic FUS causes early synaptic defects prior to aggregation in an ALS-FUS mouse model (3) and this will be the focus of this talk. Like TDP-43, FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. After determining the sub-synaptic localization of FUS using super-resolution imaging, we employed CLIP-seq on synaptoneurosomes to identify synaptic FUS RNA targets. The latter encode proteins associated with synapse organization and plasticity. Significant increase of synaptic FUS during early disease in a knock-in mouse model of ALS-FUS was accompanied by alterations in density and size of GABAergic synapses. RNAs abnormally accumulated at the synapses of 6-month-old ALS-FUS mice were enriched for FUS targets and correlated with those depicting increased short-term RNA stability via binding primarily on multiple exonic sites. Our work indicates that early synaptopathy triggered by synaptic FUS accumulation, prior to aggregation, leads to ALS-FUS and understanding the underlying molecular events will be key for devising early and effective therapeutic interventions.

1. Afroz et al...Polymenidou (2017) Nature Communications, DOI: 10.1038/s41467-017-00062-0

2. Laferriere et al...Polymenidou (2018) Nature Neuroscience, DOI: 10.1038/s41593-018-0294-y

3. Sahadevan et al...Polymenidou (2020) bioRxiv. DOI: 10.1101/2020.06.10.136010