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 expande...

Full description

Saved in:
Bibliographic Details
Published in:Neurobiology of aging 2016-03, Vol.39, p.174-183
Main Authors: Loureiro, Joana R, Oliveira, Claudia L, Silveira, Isabel
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - genetics
C9orf72 Protein
DNA Repeat Expansion
Frontotemporal dementia
Frontotemporal Dementia - genetics
FTD/ALS
Humans
Internal Medicine
Nerve Tissue Proteins - genetics
Neurodegenerative Diseases - genetics
Neurology
Nuclear Proteins - genetics
Proteins - genetics
RAN translation
RNA - genetics
RNA foci
RNA Splicing - genetics
RNA-Binding Proteins
Spinocerebellar ataxia
Spinocerebellar Ataxias - genetics
Splicing misregulation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2015.12.007