RNA-protein interactions in unstable microsatellite diseases.
A novel RNA-mediated disease mechanism has emerged from studies on dominantly inherited neurological disorders caused by unstable microsatellite expansions in non-coding regions of the genome. These non-coding tandem repeat expansions trigger the production of unusual RNAs that gain a toxic function, which involves the formation of RNA repeat structures that interact with, and alter the activities of, various factors required for normal RNA processing as well as additional cellular functions. In this review, we explore the deleterious effects of toxic RNA expression and discuss the various model systems currently available for studying RNA gain-of-function in neurologic diseases. Common themes, including bidirectional transcription and repeat-associated non-ATG (RAN) translation, have recently emerged from expansion disease studies. These and other discoveries have highlighted the need for further investigations designed to provide the additional mechanistic insights essential for future therapeutic development.
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Cancer Genetics Research Complex, 2033 Mowry Road, Gainesville, FL 32610-3610, USA.
Apoorva
A
Mohan
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Cancer Genetics Research Complex, 2033 Mowry Road, Gainesville, FL 32610-3610, USA.
Marianne
M
Goodwin
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Cancer Genetics Research Complex, 2033 Mowry Road, Gainesville, FL 32610-3610, USA. Electronic address: mswanson@ufl.edu.
Maurice S
MS
Swanson
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D001259:Ataxia / Q000235:genetics; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004195:Disease Models, Animal; D005600:Fragile X Syndrome / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D009223:Myotonic Dystrophy / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D012313:RNA / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D014202:Tremor / Q000235:genetics
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D016601:RNA-Binding Proteins; D012313:RNA
Bidirectional transcription; Microsatellite; Neurologic disease; Protein sequestration; RNA foci; RNA-mediated toxicity