Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy - 17/04/25

Doi : 10.1016/S1474-4422(25)00109-7

Rubika Balendra, MRCP PhD ^a,^b,⁎ , Jemeen Sreedharan, MRCP PhD ^c, Martina Hallegger, PhD ^d,^e,^f, Raphaëlle Luisier, PhD ^g, Hilal A Lashuel, ProfPhD ^h,ⁱ, Jenna M Gregory, ProfMB PhD ^j, Rickie Patani, ProfFRCP PhD ^a,^k,⁎

^a Human Stem Cells and Neurodegeneration Laboratory, The Francis Crick Institute, London, UK

^b UK Dementia Research Institute at UCL, London, UK

^c Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

^d UK Dementia Research Institute at King’s, London, UK

^e The Francis Crick Institute, London, UK

^f Oxford-GSK Institute of Molecular and Computational Medicine, Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK

^g Genomics and Health Informatics Group, Idiap Research Institute, Martigny, Switzerland

^h Laboratory of Molecular and Chemical Biology of Neurodegeneration, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

ⁱ Qatar Foundation, Doha, Qatar

^j Institute of Medical Sciences, University of Aberdeen, UK

^k Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, UK

^* Correspondence to: Prof Rickie Patani, Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London WC1N 3B, UK Department of Neuromuscular Disease UCL Queen Square Institute of Neurology London WC1N 3B UK ^** Correspondence to: Dr Rubika Balendra, UK Dementia Research Institute at UCL, London WC1E 6AE, UK UK Dementia Research Institute at UCL London WC1E 6AE UK

Summary

Mutations in the TARDBP gene, which encodes the TDP-43 protein, account for only 3–5% of familial cases of amyotrophic lateral sclerosis and less than 1% of cases that are apparently idiopathic. However, the discovery of neuronal inclusions of TDP-43 as the neuropathological hallmark in the majority of cases of amyotrophic lateral sclerosis has transformed our understanding of the pathomechanisms underlying neurodegeneration. An individual TARDBP mutation can cause phenotypic heterogeneity. Most mutations lie within the C-terminus of the TDP-43 protein. In pathological conditions, TDP-43 is mislocalised from the nucleus to the cytoplasm, where it can be phosphorylated, cleaved, and form insoluble aggregates. This mislocalisation leads to dysfunction of downstream pathways of RNA metabolism, proteostasis, mitochondrial function, oxidative stress, axonal transport, and local translation. Biomarkers for TDP-43 dysfunction and targeted therapies are being developed, justifying cautious optimism for personalised medicine approaches that could rescue the downstream effects of TDP-43 pathology.

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