title: Unstable repeat expansions in neurodegenerative diseases: nucleocytoplasmic transport emerges on the scene.
abstract: An astonishing number of neurological diseases result from expansion of unstable repetitive sequences causing alterations in key neuronal processes. Some are progressive late-onset conditions related to aging, such as the spinocerebellar ataxias. In several of these pathologies, the expanded repeat is transcribed, producing an expanded RNA repeat that causes neurodegeneration by a complex mechanism, comprising 3 main pathways. These include (1) accumulation in the nucleus of RNA foci, resulting from sequestration of RNA-binding proteins functioning in important neuronal cascades; (2) decrease in availability of RNA-binding proteins, such as splicing factors, causing alternative splicing misregulation with imbalance in the expression ratio of neuronal isoforms; and (3) generation of neurotoxic peptides, produced from repeat-associated non-ATG-initiated translation across the RNA repeat, in all reading frames. Recently, 2 pathologies characterized by impaired motor function, cognitive decline, or/and degeneration of motor neurons have been found that have broaden our understanding of these diseases. Moreover, the finding of compromised nucleocytoplasmic transport opens new avenues for research. This review will cover the amazing progress regarding these conditions.
authors.affiliation: Group Genetics of Cognitive Dysfunction, i3s- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal; ICBAS, Universidade do Porto, Portugal.
authors.forename: Joana R
authors.initials: JR
authors.lastname: Loureiro
authors.affiliation: Group Genetics of Cognitive Dysfunction, i3s- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal; ICBAS, Universidade do Porto, Portugal.
authors.forename: Claudia L
authors.initials: CL
authors.lastname: Oliveira
authors.affiliation: Group Genetics of Cognitive Dysfunction, i3s- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal; ICBAS, Universidade do Porto, Portugal. Electronic address: isilveir@ibmc.up.pt.
authors.forename: Isabel
authors.initials: I
authors.lastname: Silveira
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D057180:Frontotemporal Dementia / Q000235:genetics; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012313:RNA / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D016601:RNA-Binding Proteins; D020754:Spinocerebellar Ataxias / Q000235:genetics
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C486600:NOP56 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D012313:RNA
keywords: FTD/ALS; Frontotemporal dementia; RAN translation; RNA foci; Spinocerebellar ataxia; Splicing misregulation