Mutation of the ALS/FTD-associated RNA-binding protein FUS alters axonal cytoskeletal organisation

Abstract

Aberrant condensation and localisation of the RNA-binding protein fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is also associated with cytoskeletal defects, genetically and through observations of compromised axonal transport. Here, we asked whether compromised axonal cytoskeletal organisation is an early feature of FUS-associated ALS/FTD. We used an ALS-associated mutant FUS(P525L) and the FTD-mimic hypomethylated FUS, FUS(16R), to investigate the common and distinct cytoskeletal changes found in these two reported Xenopus models. Combining a novel atomic force microscopy (AFM)-based approach for in vitro cytoskeletal characterisation and in vivo axonal branching analysis, we found that mutant FUS reduced actin density in the dynamically remodelling growth cone, and reduced axonal branch complexity. We furthermore found evidence of an axon looping defect for FUS(P525L). Therefore, we show that compromised actin remodelling is potentially an important early event in FUS-associated pathogenesis.

Intracellular FUS protein accumulation leads to cytoskeletal, organelle and cellular homeostasis perturbations

“…Similar observations in neuronal models have linked axonal cytoskeletal integrity to the proteinopathy of FUS (Castellanos-Montiel et al, 2020; Giampetruzzi et al, 2019; Theunissen et al, 2021) and other FTD/ALS-implicated proteins, e.g., TAR DNA-binding protein (TDP43) (Baskaran et al, 2018; Briese et al, 2020). This includes a related study in Xenopus laevis retinal ganglion cells that demonstrated P525L-FUS reduces actin density specifically in growth cones, resulting in localised softening of the axon(van Tartwijk et al, 2022). Furthermore, several ALS-linked genes that directly impair cytoskeletal dynamics (Castellanos-Montiel et al, 2020; Garone et al, 2020).…”