Mizielinska, Sarah;
Hautbergue, Guillaume M;
Gendron, Tania F;
van Blitterswijk, Marka;
Hardiman, Orla;
Ravits, John;
Isaacs, Adrian M;
(2025)
Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics.
The Lancet Neurology
, 24
(3)
pp. 261-274.
10.1016/S1474-4422(25)00026-2.
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Mizielinska et al C9orf72 Review Lancet Neurology.pdf - Accepted Version Access restricted to UCL open access staff until 20 August 2025. Download (1MB) |
Abstract
GGGGCC repeat expansions in C9orf72 are a common genetic cause of amyotrophic lateral sclerosis in people of European ancestry; however, substantial variability in the penetrance of the mutation, age at disease onset, and clinical presentation can complicate diagnosis and prognosis. The repeat expansion is bidirectionally transcribed in the sense and antisense directions into repetitive RNAs and translated into dipeptide repeat proteins, and both accumulate in the cortex, cerebellum, and the spinal cord. Furthermore, neuropathological aggregates of phosphorylated TDP-43 are observed in motor cortex and other cortical regions, and in the spinal cord of patients at autopsy. C9orf72 repeat expansions can also cause frontotemporal dementia. The GGGGCC repeat induces a complex interplay of loss-of-function and gain-of-function pathological mechanisms. Clinical trials using antisense oligonucleotides to target the GGGGCC repeat RNA have not been successful, potentially because they only target a single gain-of-function mechanism. Novel therapeutic approaches targeting the DNA repeat expansion, multiple repeat-derived RNA species, or downstream targets of TDP-43 dysfunction are, however, on the horizon, together with the development of diagnostic and prognostic biomarkers.
| Type: | Article |
|---|---|
| Title: | Amyotrophic lateral sclerosis caused by hexanucleotide repeat expansions in C9orf72: from genetics to therapeutics |
| DOI: | 10.1016/S1474-4422(25)00026-2 |
| Publisher version: | https://doi.org/10.1016/S1474-4422(25)00026-2 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10206547 |
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