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Updated: Mar 15, 2026
Real-Time Fluorescent Measurement of Synaptic Functions in Models of Amyotrophic Lateral Sclerosis
Published on: July 16, 2021
Pathogenesis of FUS-associated ALS and FTD: insights from rodent models
Matthew Nolan1, Kevin Talbot2, Olaf Ansorge3
1Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
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.
Insights
Disruptions in the FUS gene are linked to neurodegenerative diseases like ALS and FTD. Research into FUS vertebrate models is crucial for understanding these complex conditions.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- RNA processing and homeostasis disruptions are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- Mutations in the Fused-in-Sarcoma (FUS) gene are associated with a subset of ALS cases.
- FUS and TDP-43, another ALS-related protein, share structural and functional similarities, suggesting aberrant RNA processing is key in ALS/FTD.
Purpose of the Study:
- To review the evidence for FUS pathogenicity in ALS/FTD.
- To analyze experimental approaches and phenotypic features of FUS rodent models.
- To outline the contribution of these models to understanding pathogenic mechanisms.
Main Methods:
- Review of existing literature on FUS gene mutations and their role in ALS/FTD.
- Analysis of data from transgenic vertebrate models, specifically FUS rodent models.
- Comparison of FUS and TDP-43 functions and their implications in neurodegeneration.
Main Results:
- FUS mutations are found in a small fraction of ALS patients but not directly linked to FTD.
- Transgenic vertebrate models of FUSopathy have yielded varying results.
- FUS and TDP-43 share similarities, underscoring the importance of RNA processing pathways.
Conclusions:
- FUS plays a role in the pathogenesis of ALS/FTD.
- FUS rodent models are valuable tools for studying disease mechanisms.
- Further development of vertebrate models is essential for advancing our understanding of FUS's role in neurodegenerative diseases.
