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.
Highlights
Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterised by the progressive destruction of neurons, associated with the aggregation and deposition of one or more types of proteinaceous inclusion
This review summarises our understanding of the genetic and neuropathological features of FUS-related ALS/FTD, and critically appraises the progress that has been made in modelling FUS mutations in-vivo, with a particular focus on rodent models
To our knowledge there is currently no vertebrate model that mimics the unique post-translational modifications associated with human Frontotemporal Lobar Degeneration (FTLD)-FUS, which are clearly distinct from FUSopathy with FUS mutations
Summary
Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterised by the progressive destruction of neurons, associated with the aggregation and deposition of one or more types of proteinaceous inclusion. An ‘oligogenic’ hypothesis of disease While there might be doubt about some FUS variants being directly causal, it may be speculated that they play a role as part of an oligogenic susceptibility profile, with mutations occuring in more than one ALS/FTD gene in a single patient at a higher rate than would be expected by chance This hypothesis is exemplified in lineages containing inherited mutations that display incomplete penetrance in phenotypically normal family members, where affected individuals possess risk factor variants in multiple genes. Using a novel methyl-specific antibody, they showed that inclusions in ALS-FUS are extensively asymmetrically methylated The authors used this evidence to speculate that mislocalization of FUS in ALS is caused by mutations in the NLS that are exacerbated by arginine methylation in the RGG3 domain, whereas mislocalization in FTLD-FUS may be caused more broadly by hypomethylation of all FET proteins, mediated by altered Transportin-1 binding. The lack of both motor phenotype and neurodegeneration in KO mice suggests that FUS depletion alone is
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