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Acta Neuropathol Commun. 2019 Oct 28;7(1):166. doi: 10.1186/s40478-019-0800-9.

Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss.

Author information

1
Department of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, SE5 9RT, UK.
2
West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China.
3
BRAIN Centre (Biomarker Research And Imaging for Neuroscience), Department of Neuroimaging, IoPPN, King's College London, London, UK.
4
Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK.
5
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
6
Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
7
Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK.
8
Department of Basic and Clinical Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, SE5 9RT, UK. jemeen.sreedharan@kcl.ac.uk.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a 'dying-back' disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha and TIR motif-containing 1 (Sarm1) is a key gene in the Wallerian pathway and its deletion provides long-term protection against both Wallerian degeneration and Wallerian-like, non-injury induced axonopathy, a retrograde degenerative process that occurs in many neurodegenerative diseases where axonal transport is impaired. Here, we explored whether Sarm1 signalling could be a therapeutic target for ALS by deleting Sarm1 from a mouse model of ALS-FTD, a TDP-43Q331K, YFP-H double transgenic mouse. Sarm1 deletion attenuated motor axon degeneration and neuromuscular junction denervation. Motor neuron cell bodies were also significantly protected. Deletion of Sarm1 also attenuated loss of layer V pyramidal neuronal dendritic spines in the primary motor cortex. Structural MRI identified the entorhinal cortex as the most significantly atrophic region, and histological studies confirmed a greater loss of neurons in the entorhinal cortex than in the motor cortex, suggesting a prominent FTD-like pattern of neurodegeneration in this transgenic mouse model. Despite the reduction in neuronal degeneration, Sarm1 deletion did not attenuate age-related behavioural deficits caused by TDP-43Q331K. However, Sarm1 deletion was associated with a significant increase in the viability of male TDP-43Q331K mice, suggesting a detrimental role of Wallerian-like pathways in the earliest stages of TDP-43Q331K-mediated neurodegeneration. Collectively, these results indicate that anti-SARM1 strategies have therapeutic potential in ALS-FTD.

KEYWORDS:

Amyotrophic lateral sclerosis; Axonal protection; Dendritic spines; Sterile alpha and TIR motif-containing protein 1; TAR DNA-binding protein 43; Wallerian degeneration

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