Disease Mechanisms and Therapeutic Approaches in <i>C9orf72</i> ALS-FTD
Keith Mayl,
Christopher E. Shaw,
Youn-Bok Lee
Affiliations
Keith Mayl
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, 5 Cutcombe Road, London SE5 9RT, UK
Christopher E. Shaw
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, 5 Cutcombe Road, London SE5 9RT, UK
Youn-Bok Lee
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, 5 Cutcombe Road, London SE5 9RT, UK
A hexanucleotide repeat expansion mutation in the first intron of C9orf72 is the most common known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Since the discovery in 2011, numerous pathogenic mechanisms, including both loss and gain of function, have been proposed. The body of work overall suggests that toxic gain of function arising from bidirectionally transcribed repeat RNA is likely to be the primary driver of disease. In this review, we outline the key pathogenic mechanisms that have been proposed to date and discuss some of the novel therapeutic approaches currently in development.