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

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White, Matthew A 
Lin, Ziqiang 
Kim, Eugene 
Henstridge, Christopher M 
Pena Altamira, Emiliano 

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.

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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Acta Neuropathologica Communications
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BioMed Central
Parkinson's UK (G-1602)
Wellcome Trust (210904/Z/18/Z)
J. Sreedharan gratefully acknowledges support from the Motor Neuron Disease Association, the Medical Research Council UK, the Lady Edith Wolfson Fellowship Fund, the van Geest Foundation, the Rosetrees Trust, Alzheimer’s Research UK, and the Psychiatry Research Trust. M.P.C is supported by the van Geest Foundation. We gratefully acknowledge the Chinese Scholarship Council for supporting Ziqiang Lin during this study.