Pathogenesis of FUS-associated ALS and FTD: insights from rodent models

Abstract

Disruptions to genes linked to RNA processing and homeostasis are implicated in the pathogenesis of two pathologically related but clinically heterogeneous neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in the Fused-in-Sarcoma (FUS) gene encoding a 526 amino-acid RNA-binding protein are found in a small subset of ALS cases, but FUS mutations do not appear to be a direct cause of FTD. Structural and functional similarities between FUS and another ALS-related RNA-binding protein, TDP-43, highlight the potential importance of aberrant RNA processing in ALS/FTD, and this pathway is now a major focus of interest. Recently, several research groups have reported transgenic vertebrate models of FUSopathy, with varying results. Here, we discuss the evidence for FUS pathogenicity in ALS/FTD, review the experimental approaches used and phenotypic features of FUS rodent models reported to date, and outline their contribution to our understanding of pathogenic mechanisms. Further refinement of vertebrate models will likely aid our understanding of the role of FUS in both diseases.

Keywords: Amyotrophic lateral sclerosis; FUS; FUSopathy; Frontotemporal dementia; Frontotemporal lobar degeneration; MND; TDP-43.

Fig. 1

Structure and functional domains of FUS. FUS is a member of the TET family of proteins, and contains several functional domains including a QGSY-rich region, multiple RNA binding regions, a C-terminal Zinc-finger motif and two putative ‘prion-like’ domains. The majority of mutations in ALS-FUS are located within the C-terminal nuclear localization signal domain in exon 15. Figure adapted by author from Vance et al. [91] and Deng et al. [21]

Fig. 2

Neuronal and glial cytoplasmic inclusions immunoreactive for FUS define the pathology of both ALS-FUS and FTLD-FUS. Basophilic inclusions are present in neurons in ALS-FUS (arrowed) and can be viewed using H&E stain, X400 (a). Discrete neuronal inclusion immunoreactive for FUS associated with the P525L mutation, X400 (b). ALS-FUS inclusions in the anterior horn of spinal cord, both X40 Obj (c, d). Well defined, compact inclusions (c) or intense diffuse cytoplasmic staining (d) are commonly seen, often with nuclear clearance