Pathogenesis of FUS-associated ALS and FTD: insights from rodent models.
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.
Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Matthew
0000-0002-7204-5385
M
Nolan
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Kevin
K
Talbot
Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. olaf.ansorge@ndcn.ox.ac.uk.
Olaf
O
Ansorge
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*
D034702:RNA-Binding Protein FUS
Amyotrophic lateral sclerosis; FUS; FUSopathy; Frontotemporal dementia; Frontotemporal lobar degeneration; MND; TDP-43