Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss | Acta Neuropathologica Communications | Full Text

Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss | Acta Neuropathologica Communications | Full Text

Acta Neuropathologica Communications

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

• Matthew A. White, 
• Ziqiang Lin, 
• Eugene Kim, 
• Christopher M. Henstridge, 
• Emiliano Pena Altamira, 
• Camille K. Hunt, 
• Ella Burchill, 
• Isobel Callaghan, 
• Andrea Loreto, 
• Heledd Brown-Wright, 
• Richard Mead, 
• Camilla Simmons, 
• Diana Cash, 
• Michael P. Coleman & 
• Jemeen Sreedharan 

Acta Neuropathologica Communications volume 7, Article number: 166 (2019) Cite this article

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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.