Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Amyotrophic lateral sclerosis and frontotemporal dementia form two poles of a genetically, pathologically and clinically-related disease continuum. Analysis of the genes and proteins at the heart of this continuum highlights dysfunction of RNA processing and aggrephagy as crucial disease-associated pathways. TAR DNA binding protein and fused in sarcoma (FUS) are both RNA processing proteins whose dysfunction impacts on global cellular RNA regulation. The recent discovery that expression of repeat expansions in the C9orf72 gene may induce RNA foci that could sequester RNA binding proteins such as TAR DNA binding protein and FUS highlights a further possibly important mechanism of RNA dysfunction in disease. Furthermore, sequestration of key RNA binding proteins may also play an important role in sporadic disease due to the association of TAR DNA binding protein and FUS with stress granules. In a further functional convergence, ubiquilin 2, p62, valosin-containing protein and optineurin are all linked to aggrephagy, a cargo-specific subtype of autophagy important for degrading ubiquitinated target proteins through the lysosome. Notably these two key pathways interact; TAR DNA binding protein and FUS bind and regulate key aggrephagy-related genes whereas dysfunction of aggrephagy leads to cytoplasmic relocalization and aggregation of TAR DNA binding protein. The convergence of amyotrophic lateral sclerosis and frontotemporal dementia linked genes into these two pathways highlights RNA dysfunction and aggrephagy as promising areas for drug discovery. In this review we discuss the importance of each of these pathways and suggest mechanisms by which they may cause both sporadic and familial disease.

Original publication

DOI

10.1093/brain/awt030

Type

Journal article

Journal

Brain

Publication Date

05/2013

Volume

136

Pages

1345 - 1360

Addresses

Department of Physiology, Anatomy and Genetics University of Oxford, Le Gros Clark Building, South Parks Road, Oxford OX1 3QX, UK.

Keywords

Amyotrophic Lateral Sclerosis, Animals, Autophagy, Frontotemporal Dementia, Humans, RNA Processing, Post-Transcriptional, Signal Transduction