Unstable repeat expansions in neurodegenerative diseases: nucleocytoplasmic transport emerges on the scene

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. (C) 2016 Elsevier Inc. All rights reserved.